Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000526324 | SCV001142560 | pathogenic | Li-Fraumeni syndrome | 2024-08-05 | reviewed by expert panel | curation | The NM_000546.6: c.488A>G variant in TP53 is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 163 (p.Tyr163Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). This variant has been reported in 2 additional unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs 21601526, 8164043). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000581096.5). This variant has an allele frequency of 6.196e-7 (1/1613972 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 54 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences) (PM1, PMID: 30311369). Computational predictor scores (BayesDel = 0.54; 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). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 16; VCEP specifications version 2.0; 7/24/2024) |
Gene |
RCV000115725 | SCV000149634 | pathogenic | not provided | 2022-03-02 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: loss of transcriptional activation and growth suppression activities (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12826609, 10519380, 16861262, 14559903, 26585234, 22109999, 16173033, 23929122, 20077503, 8164043, 10671690, 17559811, 17606709, 18685109, 21519010, 24651012, 17764544, 25385265, 25149524, 23967324, 17947339, 15077194, 10753186, 12792784, 15308588, 10871862, 15037740, 10567903, 29167553, 29979965, 30720243, 30630526, 30840781, 33300245, 32817165, 15510160, 21343334, 21601526, 25584008) |
Ambry Genetics | RCV000492788 | SCV000581096 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-02-09 | criteria provided, single submitter | clinical testing | The p.Y163C variant (also known as c.488A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 488. The tyrosine at codon 163 is replaced by cysteine, an amino acid with highly dissimilar properties. The p.Y163C variant has been observed as a germline alteration a patient with early-onset osteosarcoma and a family history of central nervous system malignancies (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-30). In addition, this alteration was observed in an individual from a LFS family who was diagnosed with adrenocortical carcinoma at the age of 2.5 years and an anaplastic astrocytoma at the age of 14 (Villani et. al. Lancet Oncology. 2011;12:559). This alteration has also been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer (Yi D et al. Hum. Genomics. 2019 01;13:4) This alteration is located in the functionally critical DNA binding domain of the p53 protein. In multiple yeast-based functional studies, this alteration has been shown to be devoid of transactivation capability and demonstrate dominant negative properties (Chappuis PO et al. Int. J. Cancer 1999 Dec;84(6):587-93; Kato S et al.Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis 2007 Feb;28(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Labcorp Genetics |
RCV000526324 | SCV000629829 | pathogenic | Li-Fraumeni syndrome | 2023-09-30 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the TP53 protein (p.Tyr163Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TP53-related conditions (PMID: 8164043, 11051239, 18685109, 19556618, 25584008, 25757876). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127814). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 21343334, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
Myriad Genetics, |
RCV004019613 | SCV004933439 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-14 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 23246812, 25584008]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19556618, 25584008]. |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785334 | SCV000923902 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |