Submissions for variant NM_000546.6(TP53):c.824G>C (p.Cys275Ser)

dbSNP: rs863224451

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580293	SCV000686777	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-27	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with serine at codon 275 in the DNA binding domain 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). Functional studies have reported defective transactivation and abnormal cellular proliferation in assays in yeast and human cells (PMID: 12826609, 15781620, 15781620, 29979965). However, normal function has also been reported in human assays (PMID: 30224644). This variant has been reported in an individual affected with squamous head/neck carcinoma (PMID: 21348641). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same position, p.Cys275Trp and p.Cys275Tyr, are considered to be disease-causing (ClinVar variation ID: 485044, 215997), suggesting that cysteine or similar amino acid at this position is important for the protein function. Although there is a suspicion that this variant may be associated with disease, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000580293	SCV001189861	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-09-30	criteria provided, single submitter	clinical testing	The p.C275S variant (also known as c.824G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 824. The cysteine at codon 275 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation in two tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines indicate this alteration 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). In addition, residue 275 of the p53 protein has been shown by crystal structure to be involved in DNA contact, and alteration of this residue from cysteine to serine resulted in severely decreased affinity for the target gene promoter site DNA (Martin A et al. Hum. Mutat. 2002 Feb;19(2):149-64. Schaefer K et al. Biochemistry 2015 Jan;54(3):932-41). Another alteration at this same position, p.C275Y, was identified as a germline alteration in three individuals from a Li-Fraumeni family, where the proband had a rhabadomyosarcoma at age 2, the father with sarcoma at age 34, and a paternal uncle with sarcoma at ages 22 and 27 (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar;56(3):608-15). This variant was not reported in population-based 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 majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002521506	SCV003320550	uncertain significance	Li-Fraumeni syndrome	2023-03-17	criteria provided, single submitter	clinical testing	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. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 275 of the TP53 protein (p.Cys275Ser). 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: 376583). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12034820, 12826609, 19681600, 29979965).