Variant Annotation
Available parameters and response documentation is available here
GET /lookup/chr22-29091857-G-?add-ACMG-annotation=1
{ "chromosome": "chr22", "alt": "", "ref": "G", "pos": 29091857, "variant_id": "10190220290918579001", "regions": { "uniprot_regions": { "version": "04-Oct-2024", "items": [ { "absolute_positon": 1673882360, "amino_acid": "M1-E107,E107-R148,E149-V198,V198-S228,S228-A264,D265-H282,P283-L303,L303-Q336,Y337-K365,I366-C420,C420-A459,A459-Q487,D488-Q514,P515-L543", "chromo": "chr22", "colour": "255,0,0", "description": null, "length": 54078, "position": 29083731, "protein": "CHK2_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 1673882379, "amino_acid": "M1-E107,E107-R148,E149-V198,V198-S228,S228-A264,D265-H282,P283-L303,L303-Q336,Y337-K365,I366-C420,C420-A459,A459-Q487,D488-Q514,P515-L543", "chromo": "chr22", "colour": "255,0,0", "description": null, "length": 54039, "position": 29083750, "protein": "CHK2_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 1673882383, "amino_acid": "M1-E107,E107-R148,E149-V198,V198-S228,S228-A264,D265-H282,P283-L303,L303-Q336,Y337-K365,I366-C420,C420-A459,A459-Q487,D488-Q514,P515-L543", "chromo": "chr22", "colour": "255,0,0", "description": null, "length": 54041, "position": 29083754, "protein": "CHK2_HUMAN", "type": "homo_sapiens proteome sequences", "pub_med_references": null }, { "absolute_positon": 1673888652, "amino_acid": "Y220-L486", "chromo": "chr22", "colour": "153,153,255", "description": "Protein kinase", "length": 25386, "position": 29090023, "protein": "CHK2_HUMAN", "type": "domain", "pub_med_references": null } ] } }, "variant_type": "Deletion", "cytobands": "22q12.1", "refseq_transcripts": [ { "items": [ { "name": "NM_001005735.2", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1229del", "hgvs_p1": "T410Mfs*15", "hgvs_p3": "p.(Thr410MetfsTer15)", "location": "exon 12 of 16 position 5 of 164", "coding_location": "410 of 587", "canonical": true, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_007194.4", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1100del", "hgvs_p1": "T367Mfs*15", "hgvs_p3": "p.(Thr367MetfsTer15)", "location": "exon 11 of 15 position 5 of 164", "coding_location": "367 of 544", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000404276.6", "mane_plus": null, "uniprot_id": null }, { "name": "NM_145862.2", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1013del", "hgvs_p1": "T338Mfs*15", "hgvs_p3": "p.(Thr338MetfsTer15)", "location": "exon 10 of 14 position 5 of 164", "coding_location": "338 of 515", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001257387.2", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.437del", "hgvs_p1": "T146Mfs*15", "hgvs_p3": "p.(Thr146MetfsTer15)", "location": "exon 12 of 16 position 5 of 164", "coding_location": "146 of 323", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001349956.2", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.899del", "hgvs_p1": "T300Mfs*15", "hgvs_p3": "p.(Thr300MetfsTer15)", "location": "exon 10 of 14 position 5 of 164", "coding_location": "300 of 477", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null } ], "version": "224" } ], "ensembl_transcripts": [ { "items": [ { "name": "ENST00000382580.2", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1229del", "hgvs_p1": "T410Mfs*15", "hgvs_p3": "p.(Thr410MetfsTer15)", "location": "exon 12 of 16 position 5 of 164", "coding_location": "410 of 587", "canonical": true, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "1", "ensembl_appris": "alternative2", "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000328354.6", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1100del", "hgvs_p1": "T367Mfs*15", "hgvs_p3": "p.(Thr367MetfsTer15)", "location": "exon 11 of 15 position 5 of 164", "coding_location": "367 of 544", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000348295.3", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1013del", "hgvs_p1": "T338Mfs*15", "hgvs_p3": "p.(Thr338MetfsTer15)", "location": "exon 10 of 14 position 5 of 164", "coding_location": "338 of 515", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "5", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000382565.1", "strand": "-", "coding_impact": null, "function": [ "intronic" ], "hgvs": "c.320-6603del", "hgvs_p1": "p.?", "hgvs_p3": "p.?", "location": "intron 2 of 4 position 38534 of 45136", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "-6603", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000382566.1", "strand": "-", "coding_impact": null, "function": [ "3'utr", "splicing" ], "hgvs": "c.*168del", "hgvs_p1": "p.?", "hgvs_p3": "p.?", "location": "exon 10 of 14 (3'UTR) position 5 of 164", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000382578.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.827del", "hgvs_p1": "T276Mfs*15", "hgvs_p3": "p.(Thr276MetfsTer15)", "location": "exon 9 of 13 position 5 of 164", "coding_location": "276 of 453", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000402731.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1013del", "hgvs_p1": "T338Mfs*15", "hgvs_p3": "p.(Thr338MetfsTer15)", "location": "exon 9 of 13 position 5 of 164", "coding_location": "338 of 515", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000403642.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.827del", "hgvs_p1": "T276Mfs*15", "hgvs_p3": "p.(Thr276MetfsTer15)", "location": "exon 8 of 12 position 5 of 164", "coding_location": "276 of 453", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000404276.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1100del", "hgvs_p1": "T367Mfs*15", "hgvs_p3": "p.(Thr367MetfsTer15)", "location": "exon 10 of 14 position 5 of 164", "coding_location": "367 of 544", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "1", "ensembl_appris": "principal2", "mane_select": "NM_007194.4", "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000405598.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.1100del", "hgvs_p1": "T367Mfs*15", "hgvs_p3": "p.(Thr367MetfsTer15)", "location": "exon 12 of 16 position 5 of 164", "coding_location": "367 of 544", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "5", "ensembl_appris": "principal2", "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000416671.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon", "splicing" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 12 of 16 position 5 of 164", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "1", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000417588.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon", "splicing" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 9 of 13 position 5 of 164", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "2", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000433728.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon", "splicing" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 9 of 13 position 5 of 164", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "2", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000434810.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.329del", "hgvs_p1": "T110Mfs*15", "hgvs_p3": "p.(Thr110MetfsTer15)", "location": "exon 6 of 10 position 5 of 164", "coding_location": "110 of 276", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "3", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000448511.1", "strand": "-", "coding_impact": null, "function": [ "non-coding exon", "splicing" ], "hgvs": null, "hgvs_p1": null, "hgvs_p3": null, "location": "exon 10 of 14 position 5 of 164", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": "2", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" }, { "name": "ENST00000456369.1", "strand": "-", "coding_impact": null, "function": [ "intronic" ], "hgvs": "c.261+3969del", "hgvs_p1": "p.?", "hgvs_p3": "p.?", "location": "intron 4 of 5 position 3969 of 10622", "coding_location": null, "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "3969", "ensembl_support_level": "3", "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "ENST00000544772.1", "strand": "-", "coding_impact": "frameshift", "function": [ "NMD", "coding", "splicing" ], "hgvs": "c.437del", "hgvs_p1": "T146Mfs*15", "hgvs_p3": "p.(Thr146MetfsTer15)", "location": "exon 12 of 16 position 5 of 164", "coding_location": "146 of 323", "canonical": false, "gene_symbol": "CHEK2", "splice_distance": "5", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": "O96017" } ], "version": "112" } ], "gnomad_exomes": [ { "version": "2.1.1", "filter": "PASS", "ac": 509, "an": 248982, "af": 0.002044324489320513, "ac_afr": 6, "ac_amr": 2, "ac_asj": 16, "ac_fin": 189, "ac_nfe": 286, "ac_nfe_bgr": 2, "ac_nfe_est": 1, "ac_nfe_nwe": 113, "ac_nfe_onf": 67, "ac_nfe_seu": 4, "ac_nfe_swe": 99, "ac_oth": 10, "ac_afr_male": 2, "ac_asj_male": 12, "ac_fin_male": 102, "ac_nfe_male": 152, "ac_oth_male": 6, "ac_afr_female": 4, "ac_amr_female": 2, "ac_asj_female": 4, "ac_fin_female": 87, "ac_nfe_female": 134, "ac_oth_female": 4, "ac_male": 274, "ac_female": 235, "an_afr": 15192, "an_amr": 34554, "an_asj": 10026, "an_eas": 18394, "an_eas_kor": 3818, "an_eas_jpn": 152, "an_eas_oea": 14424, "an_fin": 21648, "an_nfe": 112476, "an_nfe_bgr": 2658, "an_nfe_est": 240, "an_nfe_nwe": 41580, "an_nfe_onf": 30494, "an_nfe_seu": 11418, "an_nfe_swe": 26086, "an_oth": 6076, "an_sas": 30616, "an_afr_male": 6012, "an_amr_male": 14300, "an_asj_male": 5152, "an_eas_male": 9066, "an_fin_male": 11274, "an_nfe_male": 63092, "an_oth_male": 3196, "an_sas_male": 23072, "an_afr_female": 9180, "an_amr_female": 20254, "an_asj_female": 4874, "an_eas_female": 9328, "an_fin_female": 10374, "an_nfe_female": 49384, "an_oth_female": 2880, "an_sas_female": 7544, "an_male": 135164, "an_female": 113818, "age_hist_het_under_30": 15, "age_hist_het_30_35": 13, "age_hist_het_35_40": 22, "age_hist_het_40_45": 26, "age_hist_het_45_50": 32, "age_hist_het_50_55": 33, "age_hist_het_55_60": 57, "age_hist_het_60_65": 50, "age_hist_het_65_70": 33, "age_hist_het_70_75": 21, "age_hist_het_75_80": 13, "age_hist_het_over_80": 7, "variant_type": "mixed", "segdup": true, "original_variant": "22-29091856-AG-A", "main_data": "ƒ = 0.00204" } ], "gnomad_exomes_coverage": [ { "version": "2.1", "coverage_mean": [ 69.02899932861328 ], "coverage_median": [ 68.0 ], "coverage_20_frequency": [ 0.988921781060213 ] } ], "gnomad_genomes": [ { "version": "2.1.1", "filter": "PASS", "ac": 82, "an": 31408, "af": 0.0026107997962302597, "ac_afr": 5, "ac_asj": 2, "ac_fin": 30, "ac_nfe": 41, "ac_nfe_est": 16, "ac_nfe_nwe": 20, "ac_nfe_onf": 5, "ac_oth": 4, "ac_afr_male": 1, "ac_asj_male": 2, "ac_fin_male": 16, "ac_nfe_male": 19, "ac_oth_male": 2, "ac_afr_female": 4, "ac_fin_female": 14, "ac_nfe_female": 22, "ac_oth_female": 2, "ac_male": 40, "ac_female": 42, "an_afr": 8714, "an_amr": 848, "an_asj": 290, "an_eas": 1560, "an_fin": 3476, "an_nfe": 15432, "an_nfe_est": 4592, "an_nfe_nwe": 8596, "an_nfe_onf": 2138, "an_nfe_seu": 106, "an_oth": 1088, "an_afr_male": 5034, "an_amr_male": 434, "an_asj_male": 210, "an_eas_male": 1022, "an_fin_male": 1630, "an_nfe_male": 8622, "an_oth_male": 526, "an_afr_female": 3680, "an_amr_female": 414, "an_asj_female": 80, "an_eas_female": 538, "an_fin_female": 1846, "an_nfe_female": 6810, "an_oth_female": 562, "an_male": 17478, "an_female": 13930, "nhomalt": 1, "nhomalt_nfe": 1, "nhomalt_nfe_est": 1, "nhomalt_nfe_male": 1, "nhomalt_male": 1, "age_hist_het_under_30": 9, "age_hist_het_30_35": 4, "age_hist_het_35_40": 7, "age_hist_het_40_45": 3, "age_hist_het_45_50": 10, "age_hist_het_50_55": 10, "age_hist_het_55_60": 5, "age_hist_het_65_70": 5, "age_hist_het_70_75": 1, "age_hist_hom_55_60": 1, "segdup": true, "original_variant": "22-29091856-AG-A", "main_data": "ƒ = 0.00261" } ], "gnomad_genomes_coverage": [ { "version": "2.1", "coverage_mean": [ 31.569000244140625 ], "coverage_median": [ 31.0 ], "coverage_20_frequency": [ 0.9438459425641652 ] } ], "ncbi_clinvar2": [ { "version": "05-Dec-2024", "review_status": "criteria provided, multiple submitters, no conflicts", "review_stars": 2, "variation_id": 128042, "num_submitters": 74, "pub_med_references": [ 10617473, 11053450, 11479205, 11719428, 11967536, 12094328, 12533788, 12690581, 14648717, 14648718, 14648719, 15087378, 15095295, 15122511, 15466005, 15488637, 15492928, 15520402, 16257342, 16492927, 16880452, 17085682, 18172190, 18381420, 18759107, 19338683, 19768534, 19805189, 21779515, 21807500, 21956126, 22006311, 22058428, 22419737, 22811390, 22994785, 23109706, 23652375, 23946381, 25431674, 25583358, 26884562, 26976419, 27223485, 27269948, 27433846, 27711073, 27751358, 27798748, 28135145, 28195393, 28503720, 28514723, 28727877, 28734145, 28779002, 28802053, 28874143, 29351919, 29489754, 29522266, 29909568, 31300551, 31993860, 32119081, 32285038, 32383162, 32531112, 36222830, 37055167, 37149759 ], "clinical_significance": [ "Pathogenic" ], "last_evaluation": "20241125", "origin": null, "accessions": [ { "variation_id": 128042, "accession_id": "RCV000123265", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20140615, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Familial cancer of breast", "diseases": [ { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "normalized_cancer": [ "Breast" ], "disease_mechanism": "loss of function" } ], "review_date": 20240930, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20241002, "submission_description": [ "Criteria applied: PVS1,PS3,PS4_MOD" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20240930, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20241013, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001429484" }, { "submitter_date": 20240605, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Baylor Genetics", "review_date": 20240330, "origin": "unknown", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20240617, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001481483" }, { "submitter_date": 20240208, "submission_description": [ "This sequence change creates a premature translational stop signal (p.Thr367Metfs*15) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is present in population databases (rs555607708, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This particular variant has been well described in the literature. In a large meta-analysis comprising 16 studies including 26,488 affected individuals and 27,402 controls, women heterozygous for this variant have a relative risk for familial breast cancer of 4.8 (95% CI, 3.3-7.2). The cumulative risk at age 70 years is 37% (95% CI, 26%-56%), compared to 7.8% for the average Caucasian woman in the general population (PMID: 18172190). Although one study has reported that the c.1100del variant confers an approximate 10-fold increased risk of male breast cancer (PMID: 11967536), the results have yet to be confirmed in further studies (PMID: 14648717, 14648718, 14648719, 15488637). ClinVar contains an entry for this variant (Variation ID: 128042). For these reasons, this variant has been classified as Pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Labcorp Genetics (formerly Invitae), Labcorp", "review_date": 20240131, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0346153" } } ], "date_updated": 20240220, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000166572" }, { "submitter_date": 20230725, "submission_description": [ "This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation." ], "review_description": "Pathogenic", "submitter_name": "Myriad Genetics, Inc.", "review_date": 20230309, "origin": "unknown", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20230729, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004020171" }, { "submitter_date": 20230223, "submission_description": [ "PVS1, PS3, PS4_STR, BS1" ], "review_description": "Pathogenic", "submitter_name": "Centre for Mendelian Genomics, University Medical Centre Ljubljana", "review_date": 20221209, "origin": "germline", "method": "research", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20230225, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001368134" }, { "submitter_date": 20230301, "submission_description": [ "ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong" ], "review_description": "Pathogenic", "submitter_name": "Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein", "review_date": 20221029, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20230304, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV003806873" }, { "submitter_date": 20220927, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "BRCAlab, Lund University", "review_date": 20220826, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0346153" } } ], "date_updated": 20230401, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV002588975" }, { "submitter_date": 20221006, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "MGZ Medical Genetics Center", "review_date": 20220824, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20221015, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002581843" }, { "submitter_date": 20220210, "submission_description": [ "PVS1, PS4, PS3" ], "review_description": "Pathogenic", "submitter_name": "Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center", "review_date": 20211101, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20230805, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002061638" }, { "submitter_date": 20201210, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Department of Molecular Diagnostics, Institute of Oncology Ljubljana", "review_date": 20200402, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20210307, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001499790" }, { "submitter_date": 20221214, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Genetics and Molecular Pathology, SA Pathology", "review_date": 20191213, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "mondo": "MONDO:0016419" } } ], "date_updated": 20221217, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002761797" }, { "submitter_date": 20180820, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Mendelics", "review_date": 20180702, "origin": "unknown", "method": "clinical testing", "diseases": [ { "normalized_disease": [ "Hereditary Breast Carcinoma" ], "normalized_cancer": [ "Breast" ], "symbols": { "medgen": "C0346153" }, "names": [ "Hereditary Breast Carcinoma" ] } ], "date_updated": 20221211, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000839467" }, { "submitter_date": 20161123, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Counsyl", "review_date": 20160120, "origin": "unknown", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } } ], "date_updated": 20221224, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000488123" }, { "submitter_date": 20140808, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Pathway Genomics", "review_date": 20140724, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_disease": [ "Breast Carcinoma" ], "normalized_cancer": [ "Breast" ], "symbols": { "omim": "114480" }, "names": [ "Breast Carcinoma" ] } ], "date_updated": 20141019, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000189922" } ] }, { "variation_id": 128042, "accession_id": "RCV004528801", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240512, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND CHEK2-related disorder", "diseases": [ { "names": [ "Chek2-Related Disorder" ] } ], "review_date": 20240927, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20241002, "submission_description": [ "The CHEK2 c.1100delC variant is predicted to result in a frameshift and premature protein termination (p.Thr367Metfs*15). This variant has been reported to be causative for hereditary breast cancer and uterine serous carcinoma (Bell et al. 1999. PubMed ID: 10617473; Pennington et al. 2013. PubMed ID: 22811390). In a large Danish study, this variant was associated with a statistically-significant increased risk of breast cancer (hazard ratio [HR]: 2.08, 95% CI: 1.51-2.85) and stomach cancer (HR: 5.76, 95%CI: 2.12-15.6; Näslund-Koch et al. 2016. PubMed ID: 26884562). In another study consisting of more than 80,000 breast cancer patients and age-appropriate controls, this variant was reported to have a higher risk for estrogen receptor-positive breast cancer (Schmidt et al. 2016. PubMed ID: 27269948). In addition, this variant has been associated with prostate (Hale et al. 2014. PubMed ID: 25431674) and colorectal cancers (Wasielewski et al. 2008. PubMed ID: 18676774; Xiang et al. 2011. PubMed ID: 21807500). Functional studies have shown that the c.1100del variant impairs CHEK2 activity (Lee et al. 2001. PubMed ID: 11719428; Roeb et al. 2012. PubMed ID: 22419737). This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128042/) Loss-of-function variants in CHEK2 are known to be pathogenic. This variant is interpreted as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "PreventionGenetics, part of Exact Sciences", "review_date": 20240927, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Chek2-Related Condition" ] } ], "date_updated": 20241008, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000806862" } ] }, { "variation_id": 128042, "accession_id": "RCV004760381", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20241013, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast-ovarian cancer, familial, susceptibility to, 1", "diseases": [ { "pub_med": [ 17392385, 20065170, 15604628, 17508274, 19305347, 23788249, 23918944, 24493721, 24366376, 23188549, 25394175, 24366402, 24432435, 25356965, 26389258, 33410258, 26324357, 31429903 ], "normalized_disease": [ "Breast-Ovarian Cancer, Familial, Susceptibility to, 1", "Ovarian Cancer, Susceptibility to, 1" ], "symbols": { "orphanet": "145", "omim": "604370", "medgen": "C2676676", "mondo": "MONDO:0011450" }, "names": [ "Breast-Ovarian Cancer, Familial, Susceptibility to, 1", "Ovarian Cancer, Susceptibility to, 1", "Breast Cancer, Familial 1" ], "keyword": "Neoplasm", "normalized_cancer": [ "Ovarian Cancer, Other", "Breast" ], "disease_mechanism": "loss of function" } ], "review_date": 20240822, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20241002, "submission_description": [ "Criteria applied: PVS1,PS3,PM1" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20240822, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "diseases": [ { "symbols": { "omim": "604370" } } ], "date_updated": 20241013, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005368410" } ] }, { "variation_id": 128042, "accession_id": "RCV004691754", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240818, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND NICE approved PARP inhibitor treatment", "diseases": [ { "names": [ "Nice Approved Parp Inhibitor Treatment" ] } ], "review_date": 20240812, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240815, "submission_description": [ "PVS1,PS4" ], "review_description": "Pathogenic", "submitter_name": "Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service", "review_date": 20240812, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Nice Approved Parp Inhibitor Treatment" ] } ], "date_updated": 20240818, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005196385" } ] }, { "variation_id": 128042, "accession_id": "RCV000005932", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20130404, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Li-Fraumeni syndrome 2", "diseases": [ { "pub_med": [ 26389210, 26389258 ], "normalized_cancer": [ "TUMOR PREDISPOSITION SYNDROME 4", "CANCER PREDISPOSITION SYNDROME, CHEK2-RELATED" ], "symbols": { "orphanet": "524", "omim": "609265", "medgen": "C5882668" }, "names": [ "Li-Fraumeni Syndrome 2", "Tumor Predisposition Syndrome 4", "Cancer Predisposition Syndrome, Chek2-Related" ] } ], "review_date": 20240809, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240809, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Department of Human Genetics, Hannover Medical School", "review_date": 20240809, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "609265" } } ], "date_updated": 20240811, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005186168" }, { "submitter_date": 20241002, "submission_description": [ "Criteria applied: PVS1,PS3,PS4" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20240430, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "diseases": [ { "symbols": { "omim": "609265" } } ], "date_updated": 20241013, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV003804673" }, { "submitter_date": 20240425, "submission_description": [ "ACMG Criteria: PVS1, PS3, PS4, PP4, PP5 Variant was found in heterozygous state" ], "review_description": "Pathogenic", "submitter_name": "Institute of Immunology and Genetics Kaiserslautern", "review_date": 20240424, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003003" }, "normalized_phenotype": [ "Colon Cancer" ] } ], "diseases": [ { "symbols": { "omim": "609265" } } ], "date_updated": 20240512, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005043003" }, { "submitter_date": 20231124, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Zotz-Klimas Genetics Lab, MVZ Zotz Klimas", "review_date": 20231124, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "609265" } } ], "date_updated": 20231202, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV004171570" } ] }, { "variation_id": 128042, "accession_id": "RCV000212447", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20160603, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND not provided", "diseases": [ { "symbols": { "medgen": "C3661900" }, "names": [ "Not Provided", "None Provided" ] } ], "review_date": 20240731, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240731, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital", "review_date": 20240731, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20240804, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002552006" }, { "submitter_date": 20241010, "submission_description": [ "CHEK2: PVS1, PP1:Strong, PS4:Moderate" ], "review_description": "Pathogenic", "submitter_name": "CeGaT Center for Human Genetics Tuebingen", "review_date": 20240701, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN517202" } } ], "date_updated": 20241020, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001245712" }, { "submitter_date": 20240124, "submission_description": [ "The CHEK2 c.1100delC; p.Thr367MetfsTer15 variant (rs555607708) is a well-studied variant that was originally associated with Li-Fraumeni syndrome (Bell 1999) and has since been reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 128042). This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, in vitro functional analyses demonstrate a loss of CHEK2 kinase activity, supportive of a pathogenic effect (Lee 2001). This variant is also described as a founder variant in Northern European populations (Cybulski 2004), and is found in the Finnish European population with an allele frequency of 0.87% (219/25124 alleles) in the Genome Aggregation Database. This reduced penetrance variant is associated with an increased breast cancer risk (Bak 2014, Cybulski 2004, Cybulski 2007), and the overall lifetime breast cancer risk for CHEK2 pathogenic variants in general is 20-30% (Slavin 2015). This variant has also been associated with an increased risk of prostate cancer (Naslund-Koch 2016, Pritchard 2016, Wu 2018). There may be additional cancer risks associated with this variant but evidence is incomplete at this time. Based on available information, the c.1100delC variant is considered to be pathogenic. REFERENCES Bak A et al. A risk of breast cancer in women - carriers of constitutional CHEK2 gene mutations, originating from the North - Central Poland. Hered Cancer Clin Pract. 2014 12(1): 10. Bell DW et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999 286(5449):2528-31. Cybulski C et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004 75(6):1131-5. Cybulski C et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat. 2007 102(1):119-22. Lee SB et al. Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res. 2001 61(22):8062-7. Naslund-Koch C et al. Increased Risk for Other Cancers in Addition to Breast Cancer for CHEK2*1100delC Heterozygotes Estimated From the Copenhagen General Population Study. J Clin Oncol. 2016 Apr 10;34(11):1208-16. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Slavin TP et al. Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. Front Oncol. 2015 5:208. Wu Y et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018 Jun;78(8):607-615." ], "review_description": "Pathogenic", "submitter_name": "ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories", "review_date": 20230823, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN235283" } } ], "date_updated": 20240220, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000603087" }, { "submitter_date": 20240815, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Clinical Genetics Laboratory, Skane University Hospital Lund", "review_date": 20230505, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20240825, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005197499" }, { "submitter_date": 20240105, "submission_description": [ "PP5, PS4_moderate, PVS1" ], "review_description": "Pathogenic", "submitter_name": "Mayo Clinic Laboratories, Mayo Clinic", "review_date": 20220504, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20240126, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000691834" }, { "submitter_date": 20230712, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden", "review_date": 20211103, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20230716, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002009513" }, { "submitter_date": 20220422, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "AiLife Diagnostics, AiLife Diagnostics", "review_date": 20211011, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20220423, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002503454" }, { "submitter_date": 20230301, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Revvity Omics, Revvity", "review_date": 20201027, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20230311, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002019280" }, { "submitter_date": 20201023, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen", "review_date": 20201023, "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20201128, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001447460" }, { "submitter_date": 20231222, "submission_description": [ "The CHEK2 c.1100del (p.Thr367Metfs*15) variant (also known as c.1100delC) alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer and other cancers (PMIDs: 31993860 (2020), 29522266 (2018), 28874143 (2017), 28779002 (2017), 26884562 (2016), 27223485 (2016), 15122511 (2004), 15087378 (2004), 11719428 (2001)). Based on the available information, this variant is classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Quest Diagnostics Nichols Institute San Juan Capistrano", "review_date": 20200721, "origin": "unknown", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20240106, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000601142" }, { "submitter_date": 20210925, "submission_description": [ "Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of kinase activity (Lee 2001, Wu 2001); Case control studies suggest this variant is associated with several types of cancer, including breast, colon, prostate, gastric, renal, and thyroid (Seppala 2003, The CHEK2 Breast Cancer Consortium 2004, Cybulski 2006, Desrichard 2011, Teodorczyk 2013, Hale 2014, Ma 2014, Siolek 2015, Naslund-Koch 2016, Schmidt 2016, Couch 2017, Decker 2017, Katona 2017, Carlo 2018); This variant is associated with the following publications: (PMID: 11967536, 14648718, 18759107, 27269948, 14612911, 15122511, 17085682, 22114986, 23296741, 25431674, 23946381, 25583358, 26884562, 28418444, 28779002, 28734145, 29978187, 11719428, 11053450, 31948886, 32832836, 31980526, 32854451, 31263571, 32081490, 31447099, 32255556, 15818573, 32285038, 30777372, 31871297, 30957677, 31206626, 28514723, 31263054, 30877237, 31360903, 30612635, 30303537, 30676620, 30113427, 31159747, 30833417, 31090900, 30309722, 30322717, 29767408, 30623166, 29520813, 29445900, 30947698, 30426508, 29506128, 15095295, 30333958, 28135145, 29909963, 28727877, 25186627, 26556299, 28503720, 28802053, 27806230, 27798748, 28195393, 29489754, 28125075, 19768534, 29351919, 28944238, 29146883, 26332814, 29909568, 28874143, 25980754, 26681312, 22527104, 27083775, 26822237, 27153395, 26084796, 26641009, 27716369, 27488870, 21956126, 27751358, 28008555, 27433846, 27443514, 17661168, 16452051, 15087378, 21807500, 12690581, 14648719, 10617473, 15239132, 22006311, 23409019, 22058428, 23109706, 21876083, 22058216, 20722467, 23415889, 22811390, 19030985, 22520019, 21244692, 22691310, 22994785, 15492928, 23329222, 25835597, 24723567)" ], "review_description": "Pathogenic", "submitter_name": "GeneDx", "review_date": 20200304, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20190417, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000149889" }, { "submitter_date": 20201126, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Clinical Genetics and Genomics, Karolinska University Hospital", "review_date": 20190604, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20201212, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001450042" }, { "submitter_name": "Genome Diagnostics Laboratory, Amsterdam University Medical Center", "submitter_date": 20210824, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210825, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001806916" }, { "submitter_name": "Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute", "submitter_date": 20210920, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210926, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001906450" }, { "submitter_name": "Genome Diagnostics Laboratory, University Medical Center Utrecht", "submitter_date": 20210923, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210926, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001932166" }, { "submitter_name": "Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+", "submitter_date": 20210930, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20211002, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001954678" }, { "submitter_name": "Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center", "submitter_date": 20210921, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20211007, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001974642" }, { "submitter_name": "Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)", "submitter_date": 20210819, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210821, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001798054" }, { "submitter_name": "Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen", "submitter_date": 20210902, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20210908, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001743466" }, { "submitter_name": "GenomeConnect, ClinGen", "submitter_date": 20200420, "submission_description": [ "Variant interpretted as Pathogenic and reported most recently on 12-09-2019 by Lab or GTR ID 505849. The variant was also interpretted as pathogenic ad reported on 03-04-2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant." ], "review_description": "not provided", "diseases": [ { "names": [ "Not Provided" ] } ], "date_updated": 20200719, "clinical_significance": [ "not provided" ], "review_status": "no assertion provided", "accession_id": "SCV000607207" } ] }, { "variation_id": 128042, "accession_id": "RCV004577323", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240623, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Inherited breast cancer and ovarian cancer", "diseases": [ { "normalized_cancer": [ "Ovarian Cancer, Other" ], "names": [ "Inherited Breast Cancer Ovarian Cancer" ] } ], "review_date": 20240614, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240815, "submission_description": [ "PVS1,PS4" ], "review_description": "Pathogenic", "submitter_name": "Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service", "review_date": 20240614, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Ovarian Cancer, Other" ], "names": [ "Inherited Breast Cancer Ovarian Cancer" ] } ], "date_updated": 20240818, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005196372" }, { "submitter_date": 20240617, "submission_description": [ "PVS1,PS4" ], "review_description": "Pathogenic", "submitter_name": "Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service", "review_date": 20240425, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Ovarian Cancer, Other" ], "names": [ "Inherited Breast Cancer Ovarian Cancer" ] } ], "date_updated": 20240623, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV005061419" } ] }, { "variation_id": 128042, "accession_id": "RCV003992185", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240415, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Malignant tumor of prostate", "diseases": [ { "pub_med": [ 19042984, 24071797, 22138009, 25394175, 23659877, 26389227, 26389258, 33497248, 31829902 ], "normalized_disease": [ "Prostate Cancer", "Familial Prostate Carcinoma" ], "normalized_cancer": [ "Malignant Tumor", "Prostate" ], "symbols": { "orphanet": "1331", "medgen": "C0376358", "mondo": "MONDO:0008315", "human_phenotype_ontology": "HP:0012125" }, "names": [ "Prostate Cancer", "Familial Prostate Carcinoma" ] } ], "review_date": 20240315, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240405, "submission_description": [ "Criteria applied: PVS1,PS3,PS4_MOD" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20240315, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0012125" }, "normalized_phenotype": [ "Prostate Cancer" ] } ], "diseases": [ { "symbols": { "omim": "176807" } } ], "date_updated": 20240415, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004812116" } ] }, { "variation_id": 128042, "accession_id": "RCV003388828", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20231104, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Li-Fraumeni syndrome 1", "diseases": [ { "pub_med": [ 17392385, 20065170, 12692171, 15604628, 23788249, 24493721, 25394175, 25356965, 26389258, 26324357 ], "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "orphanet": "524", "omim": "151623", "medgen": "C1835398", "gene": "553989" }, "names": [ "Li-Fraumeni Syndrome" ] } ], "review_date": 20231026, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20231101, "submission_description": [ "Criteria applied: PVS1,PS3,PS4" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20231026, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0003002" }, "normalized_phenotype": [ "Breast Carcinoma" ] } ], "diseases": [ { "symbols": { "omim": "151623" } } ], "date_updated": 20231104, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004100720" } ] }, { "variation_id": 128042, "accession_id": "RCV003445511", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20231209, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Ovarian neoplasm", "diseases": [ { "pub_med": [ 19042984, 22964825, 23188549, 33410258, 29450531 ], "normalized_disease": [ "Ovarian Neoplasm" ], "normalized_cancer": [ "Ovary/Fallopian Tube" ], "symbols": { "medgen": "C0919267", "mesh": "D010051", "mondo": "MONDO:0021068", "human_phenotype_ontology": "HP:0100615" }, "names": [ "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasm", "Ovarian Neoplasms" ] } ], "review_date": 20230728, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20231114, "submission_description": [ "The variant CHEK2:c.1100delC, p.(Thr367fs), which is located in the coding exon 11 of the CHEK2 gene, results from a deletion of a nucleotide at position 1100. The variant causes a frameshift that results on the replace of threonine residue at protein position 367 by methionine and a premature stop codon follows after further 15 amino acids. The premature stop codon is predicted to cause protein truncation/absent and nonsense mediated decay in a gene where loss-of-function is a mechanism of disease. Multiple studies has shown that the variant is statistically significant associated to increased risk of breast and other type of cancer, including ovarian cancer (PMID: 16492927; 23109706; 21956126; 16880452; 28727877; 37055167). In one study, tumours were also detected statistically significantly more frequently in mice with the CHEK2 c.1100delC variant as compared to wild-type controls (PMID: 19805189). This variant is a known founder variant in the overall population and occurs with an allele frequency of < 1 % in gnomAD. The variant is classified as Pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Diagnostics Centre, Carl Von Ossietzky University Oldenburg", "review_date": 20230728, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "167000" } } ], "date_updated": 20231209, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV004174182" } ] }, { "variation_id": 128042, "accession_id": "RCV002463641", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20221211, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Colorectal cancer", "diseases": [ { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] } ], "review_date": 20230609, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20230816, "submission_description": [ "Criteria applied: PVS1,PS3,PS4,PM2_SUP" ], "review_description": "Pathogenic", "submitter_name": "Institute of Human Genetics, University of Leipzig Medical Center", "review_date": 20230609, "origin": "unknown", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0032317" }, "normalized_phenotype": [ "Family History Of Cancer" ] } ], "diseases": [ { "symbols": { "omim": "114500" } } ], "date_updated": 20230826, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004027697" }, { "submitter_date": 20221115, "submission_description": [ "ACMG criteria used to clasify this variant: PVS1, PS3, PS4" ], "review_description": "Pathogenic", "submitter_name": "Human Genetics Bochum, Ruhr University Bochum", "review_date": 20220701, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114500" } } ], "date_updated": 20221211, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002758585" }, { "submitter_name": "Institute of Human Genetics, University Hospital of Duesseldorf", "submitter_date": 20231128, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "not provided", "diseases": [ { "symbols": { "omim": "114500" } } ], "date_updated": 20231202, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004171175" } ] }, { "variation_id": 128042, "accession_id": "RCV000115980", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20140517, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Hereditary cancer-predisposing syndrome", "diseases": [ { "pub_med": [ 25394175 ], "normalized_disease": [ "Hereditary Neoplastic Syndrome" ], "normalized_cancer": [ "Tumor predisposition", "Cancer predisposition", "Hereditary Cancer Syndrome" ], "symbols": { "medgen": "C0027672", "mesh": "D009386", "mondo": "MONDO:0015356" }, "names": [ "Hereditary Cancer-Predisposing Syndrome", "Hereditary Neoplastic Syndrome", "Tumor Predisposition", "Cancer Predisposition", "Hereditary Neoplastic Syndrome", "Hereditary Neoplastic Syndrome" ], "keyword": "Hereditary cancer syndrome" } ], "review_date": 20230411, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20240125, "submission_description": [ "This variant deletes 1 nucleotide in exon 11 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A large meta-analysis of breast cancer case-control studies has determined that female carriers of this variant show a relative risk for familial breast cancer of 4.8 (95% CI: [3.3, 7.2]) and cumulative risk at age 70 years of 37% (95% CI: [26, 56]) vs. 7.8% for the population controls (PMID: 18172190). Another meta-analysis has also shown a significant breast cancer risk in heterozygous carriers of this variant (OR=2.75, 95% CI: [2.25, 3.36]) (PMID: 22994785). The ORs and CIs were 2.33 (95% CI: [1.79, 3.05]), 3.72 (95% CI: [2.61, 5.31]) and 2.78 (95% CI: [2.28, 3.39]), respectively, in unselected, family, early-onset breast cancer subgroups in this study. This variant has been observed in individuals affected with colorectal cancer, but whether this variant is associated with increased risk of colorectal cancer remains uncertain (PMID: 21807500, 28135145, 28734145). This variant is well documented as a breast cancer-associated variant in the literature and in the public database (ClinVar variation ID: 128042). This variant has been identified in 591/280390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org) Based on the available evidence, this variant is classified as Pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Color Diagnostics, LLC DBA Color Health", "review_date": 20230411, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20240214, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000292118" }, { "submitter_date": 20240419, "submission_description": [ "The c.1100delC (p.T367Mfs*15) alteration, located in exon 11 (coding exon 10) of the CHEK2 gene, consists of a deletion of one nucleotide at position 1100, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Clinic-based studies have estimated an approximately 2-fold increase in female breast cancer, colorectal cancer, and melanoma risk associated with this alteration (CHEK2 Breast Cancer Case-Control, 2004; Xiang, 2011; Weischer, 2012). However, a recent population-based study found a 2-fold increase in female breast cancer risk and 6-fold increase in stomach cancer risk associated with this alteration, but did not find a statistically significant association with colon cancer or melanoma (Näslund-Koch, 2016). Another study found that risk for estrogen receptor (ER) positive breast cancer was more pronounced than risk for ER-negative breast cancer and estimated that the cumulative risks for development of ER-positive and ER-negative tumors by age 80 in carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom (Schmidt, 2016). This alteration has also been reported in male breast cancer cohorts (Leedom, 2016; Hallamies, 2017), and was identified in 5/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard, 2016). This alteration is located within the kinase domain, and is reported to abolish the kinase activity of CHK2 (Wu, 2001). Based on the available evidence, this alteration is classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Ambry Genetics", "review_date": 20220427, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20240501, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000187220" }, { "submitter_date": 20230621, "submission_description": [ "Data included in classification: Deletion resulting in frameshift (PVS1_vstr) The CHEK2 Breast Cancer Consortium (https://doi.org/10.1038/ng879) 1.1% in healthy individuals/5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003) (PS4_str) Data not included in classification: Weischer et al 2008 (https://doi.org/10.1200/jco.2007.12.5922) OR 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer, OR is above 2 with lower CI ≥1.5. Wu et al., 2001 (PMID: 11053450), assay reports loss of kinase activity in functional studies." ], "review_description": "Pathogenic", "submitter_name": "Cancer Variant Interpretation Group UK, Institute of Cancer Research, London", "review_date": 20220408, "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20230701, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV003933671" }, { "submitter_date": 20220425, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Sema4, Sema4", "review_date": 20211004, "origin": "germline", "method": "curation", "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20220624, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002537022" }, { "submitter_date": 20211011, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.", "review_date": 20210927, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20211016, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001977065" }, { "submitter_date": 20200306, "submission_description": [ "This variation is a deletion of 1 nucleotide from exon 11 of the CHEK2 mRNA (c.1100delC), causing a frameshift at codon 367. This creates a premature translational stop signal 15 amino acid residues later (p.Thr367Metfs*15) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic. This variant has been well described in the literature (PMID: 18172190). The mutation database ClinVar contains an entry for this variant (Variation ID: 128042)." ], "review_description": "Pathogenic", "submitter_name": "GeneKor MSA", "review_date": 20200101, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0027672" }, "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "date_updated": 20200325, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000821726" }, { "submitter_date": 20200902, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Knight Diagnostic Laboratories, Oregon Health and Sciences University", "review_date": 20190614, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "date_updated": 20201212, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV001449028" }, { "submitter_date": 20180423, "submission_description": [ "Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity." ], "review_description": "Pathogenic", "submitter_name": "Academic Department of Medical Genetics, University of Cambridge", "review_date": 20180126, "diseases": [ { "symbols": { "medgen": "C0027672" }, "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "date_updated": 20190908, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000992228" }, { "submitter_date": 20180308, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "True Health Diagnostics", "review_date": 20171114, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "date_updated": 20171219, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000787999" }, { "submitter_name": "Hauer Lab, Department Of Pediatric Oncology, Technical University Munich", "submitter_date": 20231115, "submission_description": [ "ACMG/AMP, PVS1, PM2, PP5" ], "review_description": "Pathogenic", "origin": "germline", "method": "research", "finding": [ { "names": [ "Neoplasm" ] } ], "diseases": [ { "symbols": { "orphanet": "ORPHA140162" } } ], "date_updated": 20231209, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004174265" } ] }, { "variation_id": 128042, "accession_id": "RCV002285140", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20221001, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND multiple conditions", "diseases": [ { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "normalized_cancer": [ "Breast" ], "disease_mechanism": "loss of function" }, { "pub_med": [ 19042984, 24071797, 22138009, 25394175, 23659877, 26389227, 26389258, 33497248, 31829902 ], "normalized_disease": [ "Prostate Cancer", "Familial Prostate Carcinoma" ], "normalized_cancer": [ "Malignant Tumor", "Prostate" ], "symbols": { "orphanet": "1331", "medgen": "C0376358", "mondo": "MONDO:0008315", "human_phenotype_ontology": "HP:0012125" }, "names": [ "Prostate Cancer", "Familial Prostate Carcinoma" ] }, { "pub_med": [ 26389505, 26389258, 34043773 ], "normalized_disease": [ "Colorectal Cancer" ], "normalized_cancer": [ "Colorectal cancer", "Colorectal cancer, somatic", "Malignant Colorectal Neoplasm" ], "symbols": { "omim": "114500", "medgen": "C0346629", "mondo": "MONDO:0005575" }, "names": [ "Colorectal Cancer", "Colorectal Cancer", "Colorectal Cancer" ] } ], "review_date": 20220926, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20220926, "submission_description": [ "PVS1, PS4, PS3_Supporting" ], "review_description": "Pathogenic", "submitter_name": "HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology", "review_date": 20220926, "origin": "unknown", "method": "research", "date_updated": 20221001, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002575018" } ] }, { "variation_id": 128042, "accession_id": "RCV000591014", "review_status": "no classifications from unflagged records", "allele_id": 133499, "review_description": "no classifications from unflagged records", "clinical_significance": [ "no classifications from unflagged records" ], "date_created": 20180402, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Astrocytoma", "diseases": [ { "normalized_disease": [ "Astrocytoma (Excluding Glioblastoma)" ], "symbols": { "medgen": "C0004114", "mesh": "D001254", "mondo": "MONDO:0019781", "human_phenotype_ontology": "HP:0009592" }, "names": [ "Astrocytoma (Excluding Glioblastoma)", "Astrocytoma (Excluding Glioblastoma)" ] } ], "review_date": 20220809, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_name": "Laboratory of Molecular Neuropathology, The University of Texas Health Science Center at Houston", "submitter_date": 20180326, "submission_description": [], "review_description": "Uncertain significance", "origin": "somatic", "method": "clinical testing", "diseases": [ { "symbols": { "hpo": "HP:0009592" } } ], "date_updated": 20180402, "clinical_significance": [ "Uncertain significance" ], "review_status": "flagged submission", "accession_id": "SCV000692550" } ] }, { "variation_id": 128042, "accession_id": "RCV002291559", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20221022, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Predisposition to cancer", "diseases": [ { "normalized_cancer": [ "Predisposition to cancer" ], "names": [ "Predisposition Cancer" ] } ], "review_date": 20220524, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20221007, "submission_description": [ "The CHEK2 c.1100del (p.Thr367MetfsTer15) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has been widely reported to be associated with cancer susceptibility, including significant associations with increased risk of breast cancer in large meta-analysis studies (odds ratios ~2-5, PMID: 18172190, 22994785). This variant has also been reported in individuals with colon, prostate, gastric, kidney, and thyroid cancer (PMID: 14612911, 15087378, 15492928, 16880452, 21807500, 23296741, 25431674, 25583358, 26884562). This change has an overall frequency of 0.21% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) and has been described as a founder variant in Northern European populations (PMID: 15087378). In summary, this variant meets criteria to be classified as pathogenic with evidence indicating lower penetrance." ], "review_description": "Pathogenic", "submitter_name": "St. Jude Molecular Pathology, St. Jude Children's Research Hospital", "review_date": 20220524, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Predisposition to cancer" ], "names": [ "Predisposition Cancer" ] } ], "date_updated": 20221022, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000891024" } ] }, { "variation_id": 128042, "accession_id": "RCV002225332", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20220430, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Hereditary breast ovarian cancer syndrome", "diseases": [ { "pub_med": [ 17392385, 20065170, 12692171, 15604628, 18163131, 17508274, 19305347, 23788249, 23918944, 24493721, 24366376, 23188549, 24366402, 24432435, 25356965, 26389258, 33410258, 26324357, 31429903 ], "normalized_disease": [ "Hereditary Breast Ovarian Cancer Syndrome" ], "symbols": { "orphanet": "145", "medgen": "C0677776", "mesh": "D061325", "mondo": "MONDO:0003582" }, "names": [ "Hereditary Breast Ovarian Cancer Syndrome", "Hereditary Breast Ovarian Cancer Syndrome", "Hereditary Breast Ovarian Cancer Syndrome", "Hereditary Breast Ovarian Cancer Syndrome (Hboc)", "Breast Ovarian Cancer", "Hereditary Breast Ovarian Cancer Syndrome" ], "normalized_cancer": [ "Ovarian Cancer, Other" ], "disease_mechanism": "loss of function" } ], "review_date": 20220419, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20220426, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "National Health Laboratory Service, Universitas Academic Hospital and University of the Free State", "review_date": 20220419, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0677776" } } ], "date_updated": 20220430, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002505157" } ] }, { "variation_id": 128042, "accession_id": "RCV000500025", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20170828, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast cancer, susceptibility to", "diseases": [ { "pub_med": [ 23188549, 33410258 ], "symbols": { "medgen": "C3469522" }, "names": [ "Breast Cancer, Susceptibility" ], "normalized_cancer": [ "Breast" ], "disease_mechanism": "gain of function" } ], "review_date": 20211122, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20221205, "submission_description": [ "DNA sequence analysis of the CHEK2 gene demonstrated a single base pair deletion in exon 11, c.1100del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 15 amino acids downstream of the sequence change, p.Thr367Metfs*15. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CHEK2 protein with potentially abnormal function. In vitro functional studies have demonstrated that CHEK2 c.1100del change results in loss of kinase activity and the inability to phosphorylate Cdc25C, supportive of a pathogenic effect (PMIDs: 11719428, 11053450). This pathogenic sequence change is a well-known founder pathogenic variant with relative frequency in European populations. It is associated with an increased risk for cancer and has been described in multiple patients with CHEK2-related cancers, including breast cancer, lung cancer, thyroid cancer, gastric cancer, renal cancer, lymphoma and in individuals with possible Li-Fraumeni syndrome (PMID: 21956126, 23296741, 26884562, PMID: 26506619)." ], "review_description": "Pathogenic", "submitter_name": "Genetic Services Laboratory, University of Chicago", "review_date": 20211122, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Breast" ], "names": [ "Breast Cancer, Susceptibility" ] } ], "date_updated": 20221211, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV002070848" } ] }, { "variation_id": 128042, "accession_id": "RCV001572630", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20210821, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast carcinoma", "finding": [ { "normalized_phenotype": [ "Breast Carcinoma" ], "symbols": { "medgen": "C0678222", "mondo": "MONDO:0004989", "human_phenotype_ontology": "HP:0003002" }, "names": [ "Breast Carcinoma", "Breast Carcinoma" ] } ], "review_date": 20210819, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20210819, "submission_description": [ "Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive" ], "review_description": "Pathogenic", "submitter_name": "Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences", "review_date": 20210819, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "hp": "HP:0003002" } } ], "date_updated": 20210821, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001792259" } ] }, { "variation_id": 128042, "accession_id": "RCV001770086", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20211106, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Bone osteosarcoma", "diseases": [ { "normalized_disease": [ "Bone Osteosarcoma" ], "normalized_cancer": [ "Osteosarcoma, somatic" ], "symbols": { "orphanet": "668", "omim": "259500", "medgen": "C0585442", "mondo": "MONDO:0002629" }, "names": [ "Bone Osteosarcoma", "Bone Osteosarcoma" ] } ], "review_date": 20210726, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20211104, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Clinical Genetics Laboratory, University Hospital Schleswig-Holstein", "review_date": 20210726, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "259500" } } ], "date_updated": 20211106, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV002011794" } ] }, { "variation_id": 128042, "accession_id": "RCV001270933", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20201224, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast and/or ovarian cancer", "diseases": [ { "normalized_cancer": [ "Ovarian Cancer, Other" ], "symbols": { "medgen": "CN221562" }, "names": [ "Breast / Ovarian Cancer" ] } ], "review_date": 20210507, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20211223, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario", "review_date": 20210507, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "CN221562" } } ], "date_updated": 20220101, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV002043388" }, { "submitter_date": 20190613, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "CZECANCA consortium", "review_date": 20190611, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Ovarian Cancer, Other" ], "symbols": { "medgen": "CN221562" }, "names": [ "Breast / Ovarian Cancer" ] } ], "date_updated": 20201224, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001451737" } ] }, { "variation_id": 128042, "accession_id": "RCV001391208", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20210514, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Carcinoma of pancreas", "diseases": [ { "pub_med": [ 17060676, 24493721, 25394175 ], "normalized_disease": [ "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma" ], "symbols": { "orphanet": "1333", "medgen": "C0235974", "mesh": "C562463", "mondo": "MONDO:0005192" }, "names": [ "Exocrine Pancreatic Carcinoma", "Pancreatic Acinar Carcinoma", "Exocrine Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Familial Pancreatic Carcinoma", "Exocrine Pancreatic Carcinoma" ], "normalized_cancer": [ "Pancreas" ], "disease_mechanism": "loss of function" } ], "review_date": 20210304, "review_stars": 0, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20210511, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "CZECANCA consortium", "review_date": 20210304, "origin": "germline", "method": "case-control", "diseases": [ { "symbols": { "medgen": "C0235974" } } ], "date_updated": 20210514, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001593124" } ] }, { "variation_id": 128042, "accession_id": "RCV000587467", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20180317, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Li-Fraumeni syndrome", "diseases": [ { "pub_med": [ 17392385, 24493721, 26389210, 26389258 ], "normalized_disease": [ "Li-Fraumeni Syndrome" ], "normalized_cancer": [ "Sarcoma family syndrome of Li and Fraumeni" ], "symbols": { "omim": "151623", "medgen": "C0085390", "mondo": "MONDO:0018875" }, "names": [ "Li-Fraumeni Syndrome", "Sarcoma Family Syndrome Li Fraumeni" ] } ], "review_date": 20190725, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20190924, "submission_description": [ "Variant summary: CHEK2 c.1100delC (p.Thr367MetfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.002 in 248982 control chromosomes (gnomAD). Although this variant was found at a relatively high frequency in controls, this is a well-known founder mutation that is known to be relatively frequent in European populations. c.1100delC has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and also as risk factor for several cancer types (breast, ovarian, prostate, colon, etc.). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant leads to loss of damage response and kinase activity (Lee_2001, Roeb_2012). Eighteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic." ], "review_description": "Pathogenic", "submitter_name": "Women's Health and Genetics/Laboratory Corporation of America, LabCorp", "review_date": 20190725, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_disease": [ "Li-Fraumeni Syndrome" ], "symbols": { "medgen": "C0085390" }, "names": [ "Li-Fraumeni Syndrome" ] } ], "date_updated": 20191108, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000698761" } ] }, { "variation_id": 128042, "accession_id": "RCV000515188", "review_status": "criteria provided, single submitter", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20171111, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND multiple conditions", "diseases": [ { "pub_med": [ 15604628, 18163131, 17508274, 24366376, 24366402, 24432435, 26389210, 26389258, 34242744, 31429903 ], "normalized_disease": [ "Hereditary Breast Carcinoma" ], "symbols": { "omim": "114480", "medgen": "C0346153", "mondo": "MONDO:0016419" }, "names": [ "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma", "Hereditary Breast Carcinoma" ], "keyword": "Hereditary cancer syndrome", "normalized_cancer": [ "Breast" ], "disease_mechanism": "loss of function" }, { "pub_med": [ 26389210, 26389258 ], "normalized_cancer": [ "TUMOR PREDISPOSITION SYNDROME 4", "CANCER PREDISPOSITION SYNDROME, CHEK2-RELATED" ], "symbols": { "orphanet": "524", "omim": "609265", "medgen": "C5882668" }, "names": [ "Li-Fraumeni Syndrome 2", "Tumor Predisposition Syndrome 4", "Cancer Predisposition Syndrome, Chek2-Related" ] }, { "normalized_disease": [ "Bone Osteosarcoma" ], "normalized_cancer": [ "Osteosarcoma, somatic" ], "symbols": { "orphanet": "668", "omim": "259500", "medgen": "C0585442", "mondo": "MONDO:0002629" }, "names": [ "Bone Osteosarcoma", "Bone Osteosarcoma" ] }, { "pub_med": [ 19042984, 24071797, 22138009, 25394175, 23659877, 26389227, 26389258, 33497248, 31829902 ], "normalized_disease": [ "Prostate Cancer", "Familial Prostate Carcinoma" ], "normalized_cancer": [ "Malignant Tumor", "Prostate" ], "symbols": { "orphanet": "1331", "medgen": "C0376358", "mondo": "MONDO:0008315", "human_phenotype_ontology": "HP:0012125" }, "names": [ "Prostate Cancer", "Familial Prostate Carcinoma" ] } ], "review_date": 20170518, "review_stars": 1, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20170523, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "Fulgent Genetics, Fulgent Genetics", "review_date": 20170518, "origin": "unknown", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "114480" } }, { "symbols": { "omim": "176807" } }, { "symbols": { "omim": "259500" } }, { "symbols": { "omim": "609265" } } ], "date_updated": 20171111, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000611258" } ] }, { "variation_id": 128042, "accession_id": "RCV004556721", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20240602, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND CHEK2-related cancer predisposition", "diseases": [ { "normalized_cancer": [ "CHEK2-related cancer predisposition", "CHEK2-Related Cancer Susceptibility" ], "symbols": { "medgen": "CN377760", "mondo": "MONDO:0700271" }, "names": [ "Chek2-Related Cancer Predisposition", "Chek2-Related Cancer Susceptibility" ] } ], "review_date": 20170427, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20190201, "submission_description": [ "The CHEK2 c.1100delC (p.Thr367MetfsTer15) variant is a common variant in individuals of European origin and has been investigated in multiple studies in various cancer types. A meta-analysis of ten case-control studies, including 10,860 breast cancer cases and 9,065 controls by the CHEK2 Breast Cancer Case-Control Consortium (2004) found a statistically significant association between carrying the p.Thr367MetfsTer15 variant and increase in risk of breast cancer (OR=2.34). The association of the p.Thr367MetfsTer15 variant and increased risk of breast cancer was also supported by Bernstein et al. (2006) (OR=6.65) and Weischer et al. (2007) (OR=3.2). Weischer et al. (2007) also found an association between the variant and increased risk of prostate cancer (OR=2.3) and colorectal cancer (OR=1.6). Weischer et al. (2012) found an association of the p.Thr367MetfsTer15 variant and increased risk of malignant melanoma in both a case-control study (OR=1.79) and a meta-analysis (OR=1.81). The p.Thr367MetfsTer15 variant has also been identified in patients with Li-Fraumeni syndrome (Bell et al. 1999), colon, kidney, prostate, and thyroid cancers (Cybulski et al. 2004), ovarian cancer (Walsh et al. 2011), and uterine cancer (Pennington et al. 2013), though the associated risks for these cancers due to this variant are unclear at this time. Studies by Lee et al. (2001) found a lack of kinase activity and evidence of loss of heterozygosity in a tumor sample from a patient carrying the germline p.Thr367MetfsTer15 variant. The highest allele frequency reported in the 1000 Genomes database is 0.0202 in the Finnish population. Although an association with the p.Thr367MetfsTer15 variant and susceptibility to different cancers is widely reported, the increase in risk is low to moderate. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population." ], "review_description": "Pathogenic", "submitter_name": "Illumina Laboratory Services, Illumina", "review_date": 20170427, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "CHEK2-Related Cancer Susceptibility" ], "symbols": { "medgen": "CN239278" }, "names": [ "Chek2-Related Cancer Susceptibility" ] } ], "date_updated": 20190527, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000915968" }, { "submitter_date": 20190321, "submission_description": [ "The c.1100delC (p.Thr367fs) variant in CHEK2 has been associated with increased risk for several types of cancer, including breast, colorectal, and prostate. Me ta-analyses have reported an odds ratio of 2-4 for developing breast, colorectal , or prostate cancer, and a possibly smaller increased risk of malignant melanom a (Weischer 2008, Xiang 2011, Weischer 2012, Yang 2012, Wang 2015). In addition, animal models in mice have shown that this variant causes increased tumor forma tion in multiple cancer sites (Bahassi 2009). This variant has also been reporte d by other clinical laboratories in ClinVar (Variation ID 128042). Of note, this variant has been identified in 0.3% (319/125272) of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs 35705950). Therefore, this variant is not expected to cause highly penetrant Men delian disease. In summary, the c.1100delC (p.Thr367fs) variant is an establishe d risk factor for breast, colorectal, and prostate cancers." ], "review_description": "Pathogenic", "submitter_name": "Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine", "review_date": 20150310, "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "CHEK2-Related Cancer Susceptibility" ], "symbols": { "medgen": "CN239278" }, "names": [ "Chek2-Related Cancer Susceptibility" ] } ], "date_updated": 20180409, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000711416" }, { "submitter_name": "GenomeConnect - Invitae Patient Insights Network", "submitter_date": 20210426, "submission_description": [ "Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 9/2/2020 by Invitae, 2/22/2016 by Ambry Genetics, 12/16/2016 by Myriad, 3/4/2017 by GeneDx, and 9/11/17 by Myriad Women's Health. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information." ], "review_description": "not provided", "diseases": [ { "symbols": { "medgen": "CN239278" } } ], "date_updated": 20210718, "clinical_significance": [ "not provided" ], "review_status": "no assertion provided", "accession_id": "SCV001749628" } ] }, { "variation_id": 128042, "accession_id": "RCV000210137", "review_status": "criteria provided, multiple submitters, no conflicts", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20160320, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast and colorectal cancer, susceptibility to", "diseases": [ { "normalized_cancer": [ "Breast" ], "symbols": { "medgen": "CN068920" }, "names": [ "Breast Colorectal Cancer, Susceptibility", "Hbcc, Susceptibility" ] } ], "review_date": 20151120, "review_stars": 2, "submission_description": [], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20160303, "submission_description": [], "review_description": "Pathogenic", "submitter_name": "University of Washington Department of Laboratory Medicine, University of Washington", "review_date": 20151120, "diseases": [ { "symbols": { "medgen": "C1858433" } } ], "date_updated": 20160320, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000266067" }, { "submitter_name": "Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego", "submitter_date": 20230919, "submission_description": [ "This variant is also referred to as c.1100delC (p.Thr367MetfsTer15) (NM_007194.3) in the literature. This deletion in exon 12 of 16 causes a frameshift and a premature stop codon at residue 424 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). The c.1229del (p.Thr410MetfsTer15) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.2% (585/275092) and is present in the homozygous state at a frequency of 0.0004% (1/275092). This variant is enriched in the European (Finnish) population (MAF=0.87%). Based on two large case-control studies, the relative risk for female breast cancer associated with the c.1229del variant was 3.0 (90% CI, 2.6-3.5) (PMID: 26014596, 15122511, 23109706). Additionally, a meta-analysis reported a relative risk of 1.88 (95% C.I. 1.29-2.73) for colorectal cancer associated with the c.1229del variant (PMID: 23946381). The c.1229del variant has also been associated with an increased risk of prostate cancer (PMID: 26629066) and other cancers (PMID: 26884562, 21956126). Based on the available evidence, the c.1229del (p.Thr410MetfsTer15) variant is classified as Pathogenic." ], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "normalized_cancer": [ "Breast" ], "names": [ "Susceptibility Breast Colorectal Cancer" ] } ], "date_updated": 20231021, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV004046245" } ] }, { "variation_id": 128042, "accession_id": "RCV003333692", "review_status": "no assertion criteria provided", "allele_id": 133499, "review_description": "Pathogenic", "clinical_significance": [ "Pathogenic" ], "date_created": 20231007, "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND TUMOR PREDISPOSITION SYNDROME 4, BREAST/PROSTATE/COLORECTAL", "diseases": [ { "normalized_cancer": [ "Prostate" ], "names": [ "Tumor Predisposition Syndrome 4, Breast/Prostate/Colorectal" ] } ], "pub_med_references": [ 10617473, 11479205, 11967536, 12094328, 12533788, 12690581, 15122511, 15466005, 16257342, 17085682, 27711073, 36222830 ], "review_stars": 0, "review_date": 20061101, "submission_description": [ "In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature termination in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170).", "Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families thought to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals.", "Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men.", "In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women.", "Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer, 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men.", "Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer (see 114500) cases, which the authors called HBCC. The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene.", "To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotyped 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.", "Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival.", "Johnson et al. (2005) found that relatives of bilateral breast cancer cases who were wildtype for CHEK2 had 3 times the population risk of female breast cancer, twice the risk of prostate cancer, and a large excess of male breast cancer. Relatives of those who were carriers of CHEK2*1100delC had an even higher risk of breast cancer and prostate cancer. The results were interpreted as indicating a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. They suggested that bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast cancer genes.", "Cybulski et al. (2006) identified the 1100delC mutation in 14 (0.8%) of 1,864 Polish men with prostate cancer, in 3 (1.2%) of 249 Polish men with familial prostate cancer, and in 12 (0.2%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 5.6 for familial prostate cancer in carriers of the 1-bp deletion. The authors determined that it is a founder mutation.", "Muranen et al. (2017) genotyped 39,139 breast cancer patients (of whom 624 were 1100delC carriers) and 40,063 healthy controls (of whom 224 were 1100delC carriers) from 32 Breast Cancer Association Consortium studies and analyzed the combined risk effects of CHEK2-1100delC and 77 common variants as a polygenic risk score (PRS) and pairwise interactions. The PRS conferred odds ratios of 1.59 (95% CI, 1.21-2.09) per standard deviation for breast cancer for CHEK2-1100delC carriers and 1.58 (1.55-1.62) for noncarriers. There was no evidence of deviation for the multiplicative model. The OR for the highest quintile was 2.03 (0.86-4.78), placing them in the high-risk category, and the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk at the population average.", "Breen et al. (2022) found that heterozygotes for the c.1100delC variant had an individual risk of colorectal cancer of 0.39% by age 40 to 45 years and thus recommended decreasing their age to initiate routine colonoscopy to age 40." ], "variant_id": 10190220290918579001, "submissions": [ { "submitter_date": 20231006, "submission_description": [ "In a family with tumor predisposition syndrome-4 (TPDS4; 609265), originally diagnosed with Li-Fraumeni syndrome, Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature termination in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170).", "Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families thought to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals.", "Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men.", "In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women.", "Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer, 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men.", "Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer (see 114500) cases, which the authors called HBCC. The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene.", "To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotyped 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer.", "Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival.", "Johnson et al. (2005) found that relatives of bilateral breast cancer cases who were wildtype for CHEK2 had 3 times the population risk of female breast cancer, twice the risk of prostate cancer, and a large excess of male breast cancer. Relatives of those who were carriers of CHEK2*1100delC had an even higher risk of breast cancer and prostate cancer. The results were interpreted as indicating a multiplicative interaction between CHEK2*1100delC and other unknown susceptibility genes. They suggested that bilateral breast cancer cases and their families are likely to provide an efficient basis for identification of additional low-penetrance breast cancer genes.", "Cybulski et al. (2006) identified the 1100delC mutation in 14 (0.8%) of 1,864 Polish men with prostate cancer, in 3 (1.2%) of 249 Polish men with familial prostate cancer, and in 12 (0.2%) of 5,496 healthy controls. Data analysis yielded an odds ratio of 5.6 for familial prostate cancer in carriers of the 1-bp deletion. The authors determined that it is a founder mutation.", "Muranen et al. (2017) genotyped 39,139 breast cancer patients (of whom 624 were 1100delC carriers) and 40,063 healthy controls (of whom 224 were 1100delC carriers) from 32 Breast Cancer Association Consortium studies and analyzed the combined risk effects of CHEK2-1100delC and 77 common variants as a polygenic risk score (PRS) and pairwise interactions. The PRS conferred odds ratios of 1.59 (95% CI, 1.21-2.09) per standard deviation for breast cancer for CHEK2-1100delC carriers and 1.58 (1.55-1.62) for noncarriers. There was no evidence of deviation for the multiplicative model. The OR for the highest quintile was 2.03 (0.86-4.78), placing them in the high-risk category, and the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk at the population average.", "Breen et al. (2022) found that heterozygotes for the c.1100delC variant had an individual risk of colorectal cancer of 0.39% by age 40 to 45 years and thus recommended decreasing their age to initiate routine colonoscopy to age 40." ], "review_description": "Pathogenic", "submitter_name": "OMIM", "review_date": 20061101, "pub_med_references": [ 10617473, 11479205, 11967536, 12094328, 12533788, 12690581, 15122511, 15466005, 16257342, 17085682, 27711073, 36222830 ], "origin": "germline", "method": "literature only", "diseases": [ { "normalized_cancer": [ "Prostate" ], "names": [ "Tumor Predisposition Syndrome 4, Breast/Prostate/Colorectal" ] } ], "date_updated": 20210207, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000026114" } ] }, { "variation_id": 128042, "submissions": [ { "submitter_name": "Center for Personalized Medicine, Children's Hospital Los Angeles", "submitter_date": 20181119, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "finding": [ { "symbols": { "hp": "HP:0002583" }, "normalized_phenotype": [ "Colitis" ] }, { "symbols": { "hp": "HP:0002573" }, "normalized_phenotype": [ "Hematochezia" ] }, { "symbols": { "hp": "HP:0002037" }, "normalized_phenotype": [ "Inflammation Of The Large Intestine" ] }, { "symbols": { "hp": "HP:0001873" }, "normalized_phenotype": [ "Thrombocytopenia" ] } ], "date_updated": 20181216, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000854533" } ], "submission_description": [], "review_stars": 1, "finding": [ { "normalized_phenotype": [ "Colitis" ], "symbols": { "medgen": "C0009319", "mondo": "MONDO:0005292", "human_phenotype_ontology": "HP:0002583" }, "names": [ "Colitis" ] }, { "normalized_phenotype": [ "Inflammation Of The Large Intestine" ], "symbols": { "medgen": "C0578878", "human_phenotype_ontology": "HP:0002037" }, "names": [ "Inflammation Large Intestine" ] }, { "normalized_phenotype": [ "Hematochezia" ], "symbols": { "medgen": "C0018932", "human_phenotype_ontology": "HP:0002609" }, "names": [ "Hematochezia" ] }, { "normalized_phenotype": [ "Thrombocytopenia" ], "symbols": { "medgen": "C0040034", "mesh": "D013921", "mondo": "MONDO:0002049", "human_phenotype_ontology": "HP:0008302" }, "names": [ "Thrombocytopenia" ] } ], "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND multiple conditions", "date_created": 20181216, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 133499, "variant_id": 10190220290918579001, "review_status": "criteria provided, single submitter", "accession_id": "RCV000735378" }, { "variation_id": 128042, "submissions": [ { "submitter_name": "Genome Sciences Centre, British Columbia Cancer Agency", "submitter_date": 20170508, "submission_description": [ "Positive family history of early breast cancer (niece diagnosed at age 35). Whole genome sequencing (blood and tumor) and whole transcriptome sequencing (tumor) also revealed the germline CHEK2:c.1100delC pathogenic variant, which is considered a moderate penetrance allele for breast cancer." ], "review_description": "Pathogenic", "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0023269" } }, { "symbols": { "medgen": "CN221572" } } ], "date_updated": 20170512, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV000574565" } ], "submission_description": [], "review_stars": 0, "diseases": [ { "pub_med": [ 17954709, 23917950, 23970019, 19042984, 22138009, 23188549, 24799465, 24799487, 25488926, 23835710, 24061412, 33410258, 29939838, 29939840, 31479144, 34242744 ], "normalized_disease": [ "Breast Neoplasm" ], "symbols": { "medgen": "C1458155", "mesh": "D001943", "mondo": "MONDO:0021100", "human_phenotype_ontology": "HP:0010623" }, "names": [ "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasms" ], "normalized_cancer": [ "Breast Neoplasm, NOS", "Breast" ], "disease_mechanism": "gain of function" }, { "normalized_disease": [ "Leiomyosarcoma" ], "symbols": { "medgen": "C0023269", "mondo": "MONDO:0005058", "human_phenotype_ontology": "HP:0100243" }, "names": [ "Leiomyosarcoma" ] } ], "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND multiple conditions", "date_created": 20170512, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 133499, "variant_id": 10190220290918579001, "review_status": "no assertion criteria provided", "accession_id": "RCV000488416" }, { "variation_id": 128042, "submissions": [ { "submitter_name": "A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center", "submitter_date": 20161206, "submission_description": [], "review_description": "Pathogenic", "origin": "germline", "method": "research", "diseases": [ { "normalized_disease": [ "Breast Cancer" ], "normalized_cancer": [ "Breast" ], "symbols": { "medgen": "CN221572" }, "names": [ "Breast Cancer" ] } ], "date_updated": 20170109, "clinical_significance": [ "Pathogenic" ], "review_status": "criteria provided, single submitter", "accession_id": "SCV000492465" } ], "submission_description": [], "review_stars": 1, "diseases": [ { "pub_med": [ 17954709, 23917950, 23970019, 19042984, 22138009, 23188549, 24799465, 24799487, 25488926, 23835710, 24061412, 33410258, 29939838, 29939840, 31479144, 34242744 ], "normalized_disease": [ "Breast Neoplasm" ], "symbols": { "medgen": "C1458155", "mesh": "D001943", "mondo": "MONDO:0021100", "human_phenotype_ontology": "HP:0010623" }, "names": [ "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasm", "Breast Neoplasms" ], "normalized_cancer": [ "Breast Neoplasm, NOS", "Breast" ], "disease_mechanism": "gain of function" } ], "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Breast neoplasm", "date_created": 20170109, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 133499, "variant_id": 10190220290918579001, "review_status": "criteria provided, single submitter", "accession_id": "RCV000413386" }, { "variation_id": 128042, "submissions": [ { "submitter_name": "Department of Pathology and Laboratory Medicine, Sinai Health System", "submitter_date": 20210331, "submission_description": [ "The CHEK2 p.Thr367Metfs*15 variant was identified in 1290 of 102960 proband chromosomes (frequency: 0.013) from individuals or families with breast, prostate, and colorectal cancer and was present in 1222 of 292928 control chromosomes (frequency: 0.004) from healthy individuals (Adank 2011, Cybulski 2004, Cybulski 2006, Dong 2003, Easton 2004, Ruijs 2009, Silva 2014, Weischer 2008, Xiang 2011, Yang 2012). The variant was also identified in the following databases: dbSNP (ID: rs555607708) as \"With Pathogenic allele\", ClinVar (12x, pathogenic), Clinvitae (6x, pathogenic), Cosmic (1x, salivary gland tumour sample), and the Zhejiang Colon Cancer Database (48x). The variant was not identified in the MutDB database. The variant was identified in control databases in 585 of 275092 chromosomes at a frequency of 0.002 (Genome Aggregation Consortium Feb 27, 2017). Of note, it was identified in the Finnish population in 221 of 25794 chromosomes (freq. 0.009) and in the European population in 319 of 125272 chromosomes (freq. 0.003). The c.1100delC variant is an established breast cancer susceptibility allele and is associated with a two- to three-fold increased risk for breast cancer at a median age of 53 years (Naslund-Koch 2016). This variant is also associated with an increased risk of additional cancer types, including prostate, colon, and others (Cybulski 2004, Xiang 2011). Functional studies involving wild-type and mutant CHEK2 proteins expressed in insect cells showed that the p.Thr367Metfs*15 protein lacks kinase activity, supportive of a pathogenic effect (Wu 2001). The c.1100delC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 367 and leads to a premature stop codon 15 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the CHEK2 gene are an established mechanism of disease and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic." ], "review_description": "Pathogenic", "origin": "unknown", "method": "clinical testing", "diseases": [ { "symbols": { "mondo": "MONDO:0007254" } } ], "date_updated": 20210413, "clinical_significance": [ "Pathogenic" ], "review_status": "no assertion criteria provided", "accession_id": "SCV001549046" } ], "submission_description": [], "review_stars": 0, "finding": [ { "symbols": { "medgen": "C0006142", "mondo": "MONDO:0007254" }, "names": [ "Breast Cancer", "Breast Cancer", "Breast Cancer" ], "disease_mechanism": "loss of function" } ], "title": "NM_007194.4(CHEK2):c.1100del (p.Thr367fs) AND Malignant tumor of breast", "date_created": 20210413, "clinical_significance": [ "Pathogenic" ], "review_description": "Pathogenic", "allele_id": 133499, "variant_id": 10190220290918579001, "review_status": "no assertion criteria provided", "accession_id": "RCV001354431" } ], 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"pub_med_references": [ 14993899 ], "id": 6107, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr22:28695869 delG" }, { "functions": [ "NMD", "coding", "splicing" ], "coding_impact": "frameshift", "acmg_confirmed": false, "acmg_class": "Uncertain Significance", "acmg_reannotated": "Pathogenic", "source": "Saphetor PubMedUserEntry", "codon": 367, "gene_symbol": "CHEK2", "hgvs": "T367Mfs*15", "transcript": "NM_007194.4", "pub_med_references": [ 18172190 ], "id": 5857, "confirmedByFunctionalStudy": false, "is_lifted_over": true, "lifted_from": "chr22:28695869 delG" } ] } } ] } ], "acmg_annotation": { "version_name": "12.8.2", "gene_symbol": "CHEK2", "transcript": "NM_007194.4", "transcript_reason": "MANE select", "coding_impact": "frameshift", "verdict": { "ACMG_rules": { "benign_score": 0, "benign_subscore": "Uncertain Significance", "clinical_score": 5.267, "pathogenic_score": 17, "pathogenic_subscore": "Pathogenic", "total_score": 17, "verdict": "Pathogenic" }, "classifications": [ "PVS1", "PP5_Very Strong", "PM2_Supporting" ] }, "classifications": [ { "name": "PVS1", "met_criteria": true, "user_explain": [ "Null variant (frame-shift) in gene CHEK2, predicted to cause NMD. Loss-of-function is a known mechanism of disease (gene has 863 reported pathogenic LOF variants). The exon affects 1 functional domain: UniProt protein CHK2_HUMAN domain 'Protein kinase'. The exon contains 80 pathogenic variants. The truncated region contains 262 pathogenic variants." ] }, { "name": "PP5", "met_criteria": true, "user_explain": [ "Combined evidence strength is Very Strong (score = 9).", "Very Strong: ClinVar classifies this variant as Pathogenic, 2 stars (reviewed Nov '24, 81 submissions of which 4 are from high confidence submitters), citing 11 articles (%%PUBMED:37149759%%, %%PUBMED:37055167%%, %%PUBMED:36222830%%, %%PUBMED:32531112%%, %%PUBMED:32383162%% and 6 more).", "Supporting: VarSome users have classified this variant as Pathogenic, citing %%PUBMED:12454775%%, and as Likely Pathogenic, citing %%PUBMED:14612911%%, and as Pathogenic, citing %%PUBMED:17164383%%." ], "strength": "Very Strong" }, { "name": "PM2", "met_criteria": true, "user_explain": [ "GnomAD genomes homozygous allele count = 1 is less than 2 for AD/AR gene CHEK2, good gnomAD genomes coverage = 31.6.", "GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene CHEK2, good gnomAD exomes coverage = 69.0." ], "strength": "Supporting" } ], "gene_id": 4146, "sample_findings": { "phenotypes": "No matching phenotype found for gene CHEK2 which is associated with Acute Myeloid Leukemia, Bone Osteosarcoma, Breast And Ovarian Cancer, Breast Cancer and 11 more, according to ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype.", "mode_of_inheritance": "AD/AR, based on gene information from ClinGen Disease Validity, GenCC, Mondo, PanelApp and gene2phenotype." } }, "phylop100way": [ { "version": "13-Apr-2021", "conservation_score": [ "8.738" ] } ], "maxentscan": null }