Submissions for variant NM_000546.6(TP53):c.725G>A (p.Cys242Tyr)

gnomAD frequency: 0.00001  dbSNP: rs121912655

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129809	SCV000184623	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-30	criteria provided, single submitter	clinical testing	The p.C242Y (also known as c.725G>A) pathogenic mutation is located in coding exon 6 of the TP53 gene. This variant results from a G to A substitution at nucleotide position 725, and the cysteine at codon 242 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation is located in the functionally critical DNA binding domain and is one of four amino acid residues required for zinc binding and protein stabilization (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). This p.C242Y 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) and has been detected in multiple individuals/families satisfying criteria for Li-Fraumeni syndrome (Blanco A et al. Clin Genet. 2010 Feb;77(2):193-6; Metzger AK et al. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7825-9; McIntyre JF et al. J Clin Oncol. 1994 May;12(5):925-30; Ambry internal data). This variant is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Rainwater R et al. Mol. Cell. Biol. 1995 Jul;15(7):3892-903). In addition, another missense alteration at codon 242, p.C242R, has been reported as pathogenic in a woman with the following clinical history: phyllodes breast tumor at age 22, liposarcoma at age 26, contralateral breast cancer at age 29 and ipsilateral recurrence within the radiation field at age 33, and chest wall angiosarcoma at age 35 (Heymann S et al. Radiat Oncol. 2010 Nov 8;5:104). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231770	SCV000285209	pathogenic	Li-Fraumeni syndrome	2024-12-17	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 242 of the TP53 protein (p.Cys242Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome associated tumors (PMID: 1679237, 8164043, 9839505, 19930417, 25896519, 27276934; internal data). ClinVar contains an entry for this variant (Variation ID: 12354). 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: 2531845, 2554494, 8023157, 9364015, 11429705, 12726864, 12826609, 12917626, 20407015, 21343334). This variant disrupts the p.Cys242 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 18511570, 20805372, 21059199, 25896519), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV002247332	SCV002519888	pathogenic	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000129809	SCV002582470	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288484	SCV002583130	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003314552	SCV004014206	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	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; Observed in individuals with personal histories consistent with Li-Fraumeni syndrome in published literature and tested at GeneDx (Metzger et al., 1991; McIntyre et al., 1994; Murakawa et al., 1998; Blanco et al., 2010; Mirabello et al., 2015); Published functional studies demonstrate a damaging effect: non-functional transactivation, impaired growth suppression activity, dominant-negative effect (Campomenosi et al., 2001; Kato et al., 2003; Monti et al., 2011; Kotler et al., 2018; Giacomelli et al., 2018); This variant is associated with the following publications: (PMID: 23531339, 20557307, 25529192, 22941189, 29979965, 17606709, 21349819, 9839505, 12826609, 1679237, 21348641, 19930417, 23200980, 23973117, 27267833, 25232094, 25695693, 22983585, 12112531, 27739435, 17962810, 21343334, 25847421, 22047961, 27121307, 15388804, 11429705, 21197471, 16622896, 11596036, 12957544, 25593300, 8164043, 20407015, 25896519, 9364015, 10089074, 30720243, 30840781, 31206626, 30224644, 15510160, 31105275)
Neuberg Centre For Genomic Medicine, NCGM	RCV002288484	SCV004048073	pathogenic	Li-Fraumeni syndrome 1		criteria provided, single submitter	clinical testing	The missense variant c.725G>A (p.Cys242Tyr) in TP53 gene has been reported in literature (Chang MT et.al.,2016). This pathogenic mutation is located in the functionally critical DNA binding domain, and it is one of four amino acid residues required for zinc binding and protein stabilization (Cho Y et al.). This variant has been reported to the ClinVar database as Pathogenic. The p.Cys242Tyr variant is reported with allele frequency of 0% in gnomAD exomes and novel in 1000 Genomes. The amino acid Cys at position 242 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys242Tyr in TP53 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129809	SCV004359987	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 242 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 disrupted function in yeast transactivation assays (PMID: 12826609), human cell proliferation assays (PMID: 29979965), and human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 1679237, 19930417, 32179180), individuals that met Chompret criteria (PMID: 8164043; IARC database), and individuals affected with breast cancer (PMID: 19147582, 29958926, 31168460, 32126783, 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants occurring at the same codon, p.Cys242Trp and p.Cys242Phe, are well documented pathogenic mutations (Clinvar Variation ID: 376578, 376580), indicating that cysteine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV002288484	SCV004931268	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	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].
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000129809	SCV005407746	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-02	criteria provided, single submitter	clinical testing	c.725G>A, located in exon 7 of the TP53 gene, is predicted to result in the substitution of Cysteine by Tyrosine at codon 242, p.(Cys242Arg). This variant is found in 1/147662 alleles at a frequency of 0.0007% in the gnomAD v3.1.2 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.6) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 2 Chompret individuals, which awards 1 point to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 9839505, 19930417) (PS4_supporting). It has been reported in ClinVar (4x as pathogenic, 12x as likely pathogenic), LOVD (1x NA) and CancerHotspots (12 somatic observations, PM1). Based on the currently available information, c.725G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
OMIM	RCV000013148	SCV000033395	pathogenic	Li-fraumeni-like syndrome	1995-01-01	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785282	SCV000923850	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research