Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000472593 | SCV000545350 | pathogenic | Li-Fraumeni syndrome | 2022-03-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr220 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18307025, 19101993, 20028212, 20407015, 24603336). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 15977174, 21343334). 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: 12383). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-associated cancers (PMID: 15977174, 17606709, 19556618, 20234365). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 220 of the TP53 protein (p.Tyr220Ser). |
Ambry Genetics | RCV003162249 | SCV003856751 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-11-11 | criteria provided, single submitter | clinical testing | The p.Y220S pathogenic mutation (also known as c.659A>C), located in coding exon 5 of the TP53 gene, results from an A to C substitution at nucleotide position 659. The tyrosine at codon 220 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in individuals with personal histories of Li Fraumeni syndrome core cancers including breast cancer, osteosarcoma and central nervous system tumors (Joachim T et al. Int J Cancer, 2001 Oct;94:218-21; Gonzalez KD et al. J Med Genet, 2009 Oct;46:689-93; Melhem-Bertrandt A et al. Cancer, 2012 Feb;118:908-13). 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). This variant has been 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). Another alteration at the same codon, p.Y220H (c.658T>C), has also been detected in individuals at an allele fraction that is suggestive of clonal hematopoiesis and is anticipated to result in a decrease in structural stability (Ambry internal data; Cho Y, Science 1994 Jul; 265(5170):346-55). This amino acid position is highly conserved in available vertebrate species. The p.Y220S variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. |
Myriad Genetics, |
RCV000013183 | SCV004933438 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. 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: 15977174, 19556618]. |
Gene |
RCV004719642 | SCV005324865 | pathogenic | not provided | 2024-01-22 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression ability (PMID: 12826609, 30224644, 29979965, 21343334); Observed in individuals with TP53-related cancers (PMID: 19556618, 11668501); 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: 30720243, 30840781, 34273903, 10567903, 21121188, 24603336, 29979965, 26619011, 15510160, 17606709, 11668501, 12826609, 22768918, 32817165, 19556618, 30224644, 21343334) |
OMIM | RCV000013183 | SCV000033430 | pathogenic | Li-Fraumeni syndrome 1 | 2005-08-01 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785481 | SCV000924053 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |