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Fraumeni"]}],"review_date":20240906,"review_stars":3,"submission_description":[],"variant_id":10190170075784060001,"submissions":[{"submitter_date":20240906,"submission_description":["The NM_000546.6: c.524G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 175 (p.Arg175Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PM2_Supporting, BS3_Supporting, PP3_Moderate, PP4, PM1, PM5 (Bayesian Points: 9; VCEP specifications version 2.0; 9/6/2024)"],"review_description":"Likely Pathogenic","submitter_name":"ClinGen TP53 Variant Curation Expert Panel, ClinGen","review_date":20240906,"origin":"germline","method":"curation","diseases":[{"symbols":{"mondo":"MONDO:0018875"}}],"date_updated":20240916,"clinical_significance":["Likely Pathogenic"],"review_status":"reviewed by expert panel","accession_id":"SCV005201130"},{"submitter_date":20240208,"submission_description":["For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 16707427, 16861262). 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. ClinVar contains an entry for this variant (Variation ID: 182963). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 16707427; Invitae). This variant is not present in population databases (gnomAD no frequency). 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)."],"review_description":"Pathogenic","submitter_name":"Labcorp Genetics (formerly Invitae), Labcorp","review_date":20220816,"origin":"germline","method":"clinical testing","diseases":[{"symbols":{"medgen":"C0085390"}}],"date_updated":20240214,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000951018"}]},{"variation_id":182963,"accession_id":"RCV000161065","review_status":"criteria provided, multiple submitters, no conflicts","allele_id":181010,"review_description":"Pathogenic/Likely pathogenic","clinical_significance":["Pathogenic","Likely pathogenic"],"date_created":20150224,"title":"NM_000546.6(TP53):c.524G>T (p.Arg175Leu) 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":20220618,"review_stars":2,"submission_description":[],"variant_id":10190170075784060001,"submissions":[{"submitter_date":20221006,"submission_description":[],"review_description":"Likely pathogenic","submitter_name":"Genome-Nilou Lab","review_date":20220618,"origin":"germline","method":"clinical testing","diseases":[{"names":["Hereditary Cancer-Predisposing Syndrome"]}],"date_updated":20221015,"clinical_significance":["Likely pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002582385"},{"submitter_date":20240424,"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_description":"Pathogenic","submitter_name":"Ambry Genetics","review_date":20200917,"origin":"germline","method":"clinical testing","diseases":[{"symbols":{"medgen":"C0027672"}}],"date_updated":20240501,"clinical_significance":["Pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV000275440"}]},{"variation_id":182963,"accession_id":"RCV002288703","review_status":"criteria provided, single submitter","allele_id":181010,"review_description":"Likely pathogenic","clinical_significance":["Likely pathogenic"],"date_created":20221015,"title":"NM_000546.6(TP53):c.524G>T (p.Arg175Leu) 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":20220618,"review_stars":1,"submission_description":[],"variant_id":10190170075784060001,"submissions":[{"submitter_date":20221006,"submission_description":[],"review_description":"Likely pathogenic","submitter_name":"Genome-Nilou Lab","review_date":20220618,"origin":"germline","method":"clinical testing","diseases":[{"symbols":{"omim":"151623"}}],"date_updated":20221015,"clinical_significance":["Likely pathogenic"],"review_status":"criteria provided, single submitter","accession_id":"SCV002583047"}]}],"main_data":"likely pathogenic **3**","names":["NM_000546.6(TP53):c.524G>T (p.Arg175Leu)","NM_000546.6(TP53):c.524G>T"],"variant_type":"SNV"}],"iarc_tp53_germline":[{"version":"release 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Other clinical definitions for LFS have been proposed and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.","disease_symbol":null,"disease_alt_symbol":null,"evidences":{"pub_med_references":[1565144,1737852,1933902,1978757,2259385,7887414,8825920,9452042,10484981,36108750],"cosmic_study":null}},{"disease":"Li-Fraumeni syndrome 1 ","disease_description":"Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies.","disease_symbol":null,"disease_alt_symbol":null,"evidences":{}}],"siftscore":null,"siftprediction":null,"polyphenscore":null,"polyphenprediction":null,"evidences":null,"xrefs":{"cosmicmutationid":["COSV52731306"],"clinvaraccession":[]},"variant_type":"Disease","disease":"Hereditary cancer-predisposing 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syndrome","evidence_met":["BS3_Supporting","PS4_Moderate","PP3_Moderate","PP4","PM1","PM5","PM2_Supporting"],"evidence_not_met":["BA1","BP4","PS3","PS2","PS1","BS1","PP1","BS2"],"expert_panel":"TP53 VCEP","guideline":null,"mode_of_inheritance":"Autosomal dominant inheritance","mondo_id":"MONDO:0018875","pathogenicity":"Likely Pathogenic","pub_med_references":null,"published_date":"2024-09-06","repo_link":"https://erepo.genome.network/evrepo/ui/classification/CA000252/MONDO:0018875/009","retracted":"false","summary":"The NM_000546.6: c.524G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 175 (p.Arg175Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PM2_Supporting, BS3_Supporting, PP3_Moderate, PP4, PM1, PM5 (Bayesian Points: 9; VCEP specifications version 2.0; 9/6/2024)"}]}