Submissions for variant NM_000546.6(TP53):c.422G>A (p.Cys141Tyr)

dbSNP: rs587781288

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128975	SCV000172861	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.C141Y pathogenic mutation (also known as c.422G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 422. The cysteine at codon 141 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported several times in families either meeting diagnostic criteria for Li-Fraumeni syndrome (LFS) or in families with features suggestive of LFS (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8). This mutation is located in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and reduced DNA-binding in yeast-based assays compared to wildtype p53 protein (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and is deficient at growth suppression (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 considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472876	SCV000545264	pathogenic	Li-Fraumeni syndrome	2024-11-22	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 141 of the TP53 protein (p.Cys141Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast cancer, Li-Fraumeni syndrome (LFS)-related cancers (liposarcoma, astrocytoma, Hodgkin lymphoma), and in families with a strong history of LFS-related cancers (PMID: 10589545, 11370630, 20522432, 21232794; internal data). ClinVar contains an entry for this variant (Variation ID: 140801). 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, 16861262, 20128691, 21343334, 24256616). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001582600	SCV001812334	pathogenic	not provided	2020-09-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: loss of transactivation and cell growth suppression abilities (Kato 2003, Dearth 2007, Monti 2011, Malcikova 2010, Kotler 2018); Not observed in large population cohorts (Lek 2016); 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: 33138793, 31105275, 10589545, 31206626, 18511570, 26619011, 24256616, 21232794, 20522432, 11370630, 30840781, 30720243, 28975465, 28152038, 29979965, 17606709, 20128691, 16861262, 12826609, 21343334)
Genome-Nilou Lab	RCV000128975	SCV002582604	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288619	SCV002583165	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288619	SCV004930458	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: 8816796, 9418900]. 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: 11370630, 20522432].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000128975	SCV006059695	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785510	SCV000924082	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research