Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV001069143 | SCV007449468 | likely pathogenic | Li-Fraumeni syndrome | 2025-11-07 | criteria provided, single submitter | clinical testing | Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is predicted to alter protein function or structure, or disrupt splicing by multiple in silico tools (ACMG/AMP: PP3_Moderate). |
| Molecular Pathology, |
RCV001069143 | SCV006276546 | likely pathogenic | Li-Fraumeni syndrome | 2024-04-29 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV004019738 | SCV004933960 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-13 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 16247456, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Ce |
RCV000581322 | SCV001335063 | pathogenic | not provided | 2020-03-01 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001069143 | SCV001234291 | uncertain significance | Li-Fraumeni syndrome | 2025-06-30 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 135 of the TP53 protein (p.Cys135Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer at an allele fraction of 0.16 (PMID: 30630526). ClinVar contains an entry for this variant (Variation ID: 141762). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Color Diagnostics, |
RCV000130396 | SCV000686738 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-14 | criteria provided, single submitter | clinical testing | This missense variant replaces cysteine with tyrosine at codon 135 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant yields protein that is non-functional in yeast transactivation assays (PMID: 12826609, 15017592, 16861262, 20407015), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 16247456, 30224644). This variant has been reported in a Chinese individual affected with gastric cancer (PMID: 21080251) and in a Chinese individual with sporadic triple-negative breast cancer carrying a second variant in MSH6 (PMID: 30630526). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV000130396 | SCV000185255 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-22 | criteria provided, single submitter | clinical testing | The p.C135Y pathogenic mutation (also known as c.404G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 404. The cysteine at codon 135 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in one Chinese patient diagnosed with sporadic triple negative breast cancer; this individual also carried a likely pathogenic variant in the MSH6 gene (Yi D et al. Hum. Genomics. 2019 01;13:4). This variant 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). This variant was detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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; Jordan JJ et al. Mol. Cancer Res. 2010 May;8(5):701-16). 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). Internal structural analysis suggests this variant, which is a buried residue in the secondary shell of the DNA binding surface, is structurally destabilizing (Cho Y et al. Science. 1994 Jul 15;265(5170):346-55; Ambry internal data). 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 variant is interpreted as a disease-causing mutation. |
| Mayo Clinic Laboratories, |
RCV000581322 | SCV000692089 | likely pathogenic | not provided | no assertion criteria provided | clinical testing |