Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV000492197 | SCV006059703 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-12-10 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV004020511 | SCV004931622 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | 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]. |
| Ambry Genetics | RCV000492197 | SCV000581114 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-02-04 | criteria provided, single submitter | clinical testing | The p.Y234D pathogenic mutation (also known as c.700T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 700. The tyrosine at codon 234 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been detected in individuals meeting clinical criteria for classic Li-Fraumeni syndrome (Ambry internal data). 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;100:8424-9). 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). In addition, this alteration is predicted to be deleterious by in silico analysis. Two other alterations at the same codon, p.Y234H and p.Y234S, have been reported in families with Li-Fraumeni syndrome (Mitchell G et al. PLoS ONE 2013 ; 8(7):e69026; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV000204217 | SCV000259812 | pathogenic | Li-Fraumeni syndrome | 2024-08-22 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 234 of the TP53 protein (p.Tyr234Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with chronic lymphocytic leukemia and/or clinical features of Li-Fraumeni syndrome (PMID: 21232794; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219759). 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%. For these reasons, this variant has been classified as Pathogenic. |