Variant Annotation
Available parameters and response documentation is available here
GET /lookup/TP53:R175L?add-all-data=1
{ "chromosome": "chr17", "alt": "A", "ref": "C", "pos": 7578406, "variant_id": "10190170075784060001", "variant_type": "SNV", "cytobands": "17p13.1", "refseq_transcripts": [ { "items": [ { "name": "NM_001276760.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.407G>T", "hgvs_p1": "R136L", "hgvs_p3": "p.Arg136Leu", "location": "exon 5 of 11 position 149 of 184", "coding_location": "136 of 355", "canonical": true, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_000546.6", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.524G>T", "hgvs_p1": "R175L", "hgvs_p3": "p.Arg175Leu", "location": "exon 5 of 11 position 149 of 184", "coding_location": "175 of 394", "canonical": false, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": "ENST00000269305.9", "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126112.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.524G>T", "hgvs_p1": "R175L", "hgvs_p3": "p.Arg175Leu", "location": "exon 5 of 11 position 149 of 184", "coding_location": "175 of 394", "canonical": false, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126113.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.524G>T", "hgvs_p1": "R175L", "hgvs_p3": "p.Arg175Leu", "location": "exon 5 of 12 position 149 of 184", "coding_location": "175 of 347", "canonical": false, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001126114.2", "strand": "-", "coding_impact": "missense", 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"ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276695.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.407G>T", "hgvs_p1": "R136L", "hgvs_p3": "p.Arg136Leu", "location": "exon 5 of 12 position 149 of 184", "coding_location": "136 of 308", "canonical": false, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276696.2", "strand": "-", "coding_impact": "missense", "function": [ "coding" ], "hgvs": "c.407G>T", "hgvs_p1": "R136L", "hgvs_p3": "p.Arg136Leu", "location": "exon 5 of 12 position 149 of 184", "coding_location": "136 of 303", "canonical": false, "gene_symbol": "TP53", "splice_distance": "-36", "ensembl_support_level": null, "ensembl_appris": null, "mane_select": null, "mane_plus": null, "uniprot_id": null }, { "name": "NM_001276697.2", "strand": "-", 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"review_stars": 1, "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" ] } ], "submissions": [ { "submitter_name": "Invitae", "review_status": "criteria provided, single submitter", "submitter_date": 20230106, "review_description": "Pathogenic", "submission_description": [ "This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 175 of the TP53 protein (p.Arg175Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 16707427; Invitae). ClinVar contains an entry for this variant (Variation ID: 182963). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 16707427, 16861262). This variant disrupts the p.Arg175 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8164043, 8825920, 11370630, 21761402, 22006311, 25927356). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic." ], "review_date": 20220816, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0085390" } } ], "date_updated": 20230207, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000951018" } ], "review_date": 20220816, "submission_description": [], "review_description": "Pathogenic", "review_status": "criteria provided, single submitter", "accession_id": "RCV000810785", "title": "NM_000546.6(TP53):c.524G>T (p.Arg175Leu) AND Li-Fraumeni syndrome" }, { "variation_id": 182963, "variant_id": 10190170075784060001, "allele_id": 181010, "clinical_significance": [ "Pathogenic", "Likely pathogenic" ], "date_created": 20150224, "review_stars": 2, "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" ], "keyword": "Hereditary cancer syndrome" } ], "submissions": [ { "submitter_name": "Genome-Nilou Lab", "review_status": "criteria provided, single submitter", "submitter_date": 20221006, "review_description": "Likely pathogenic", "submission_description": [], "review_date": 20220618, "origin": "germline", "method": "clinical testing", "diseases": [ { "names": [ "Hereditary Cancer-Predisposing Syndrome" ] } ], "date_updated": 20221015, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV002582385" }, { "submitter_name": "Ambry Genetics", "review_status": "criteria provided, single submitter", "submitter_date": 20221111, "review_description": "Pathogenic", "submission_description": [ "The p.R175L pathogenic mutation (also known as c.524G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 524. The arginine at codon 175 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been identified in pediatric patients with adrenal cortical carcinoma and in families meeting Chompret criteria for Li-Fraumeni syndrome (West AN et al. Cancer Res. 2006 May; 66(10):5056-62; Ambry internal data). This alteration is located in the DNA binding domain and has shown a partial loss of transactivation activity, and temperature sensitivity in yeast and mammalian cell in vitro assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98). More extensive evaluation of this variant showed that it was able to suppress cell growth similar to wild type p53, yet was deficient in apoptotic activity (West AN et al. Cancer Res. 2006 May; 66(10):5056-62). Structural modeling by this same group determined that the leucine substitution may destabilize the native structure, yet not necessarily disrupt the overall conformation of the DNA binding domain. Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at this same position, p.R175H, is a well-characterized mutation hotspot known to be associated with classic Li-Fraumeni syndrome (McIntyre et al. J Clin Oncol. 1994. 12(5):925-930; Melhem-Bertrandt et al. Cancer. 2012. 118(4):908-13; Choong et al. Clin Genet. 2012. 82(6):564-8; Varley et al. J Med Genet. 1995. 32:942-945). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation." ], "review_date": 20200917, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "medgen": "C0027672" } } ], "date_updated": 20221129, "clinical_significance": [ "Pathogenic" ], "accession_id": "SCV000275440" } ], "review_date": 20220618, "submission_description": [], "review_description": "Pathogenic/Likely pathogenic", "review_status": "criteria provided, multiple submitters, no conflicts", "accession_id": "RCV000161065", "title": "NM_000546.6(TP53):c.524G>T (p.Arg175Leu) AND Hereditary cancer-predisposing syndrome" }, { "variation_id": 182963, "variant_id": 10190170075784060001, "allele_id": 181010, "clinical_significance": [ "Likely pathogenic" ], "date_created": 20221015, "review_stars": 1, "diseases": [ { "pub_med": [ 17392385, 20065170, 12692171, 15604628, 23788249, 24493721, 25394175, 25356965, 26389258, 26324357 ], "normalized_disease": [ "Li-Fraumeni Syndrome 1" ], "symbols": { "orphanet": "524", "omim": "151623", "medgen": "C1835398", "gene": "553989" }, "names": [ "Li-Fraumeni Syndrome 1" ] } ], "submissions": [ { "submitter_name": "Genome-Nilou Lab", "review_status": "criteria provided, single submitter", "submitter_date": 20221006, "review_description": "Likely pathogenic", "submission_description": [], "review_date": 20220618, "origin": "germline", "method": "clinical testing", "diseases": [ { "symbols": { "omim": "151623" } } ], "date_updated": 20221015, "clinical_significance": [ "Likely pathogenic" ], "accession_id": "SCV002583047" } ], "review_date": 20220618, "submission_description": [], "review_description": "Likely pathogenic", "review_status": "criteria provided, single submitter", "accession_id": "RCV002288703", "title": "NM_000546.6(TP53):c.524G>T (p.Arg175Leu) AND Li-Fraumeni syndrome 1" } ], "main_data": "likely pathogenic, pathogenic **2**", "names": [ "NM_000546.6(TP53):c.524G>T (p.Arg175Leu)" ], "variant_type": 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