Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001023834 | SCV001185764 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-08-22 | criteria provided, single submitter | clinical testing | The p.C176G pathogenic mutation (also known as c.526T>G), located in coding exon 4 of the TP53 gene, results from a T to G substitution at nucleotide position 526. The cysteine at codon 176 is replaced by glycine, an amino acid with highly dissimilar properties. 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 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 U S A, 2003 Jul;100:8424-9). This variant has been detected in at least two individuals 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 considered to be rare based on population 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 variant is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV003621529 | SCV004489887 | uncertain significance | Li-Fraumeni syndrome | 2023-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 176 of the TP53 protein (p.Cys176Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376571). 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. 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. |
| Myriad Genetics, |
RCV004022204 | SCV004933051 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-14 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID:29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785535 | SCV000924107 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |