ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.824G>C (p.Cys275Ser) (rs863224451)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc 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.
Database of Curated Mutations (DoCM) RCV000441960 SCV000507856 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425744 SCV000507857 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436480 SCV000507858 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419235 SCV000507859 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426441 SCV000507860 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437115 SCV000507861 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419912 SCV000507862 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430590 SCV000507863 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441335 SCV000507864 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420599 SCV000507865 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431286 SCV000507866 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438476 SCV000507867 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423990 SCV000507868 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434260 SCV000507869 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441019 SCV000507870 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423341 SCV000507871 likely pathogenic Adrenocortical carcinoma 2016-05-31 no assertion criteria provided literature only

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