Submissions for variant NM_000546.6(TP53):c.733G>C (p.Gly245Arg)

dbSNP: rs28934575

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000633351	SCV000754573	uncertain significance	Li-Fraumeni syndrome	2019-12-29	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. Different missense substitutions at this codon (p.Gly245Val, p.Gly245Ser, and p.Gly245Asp) have been determined to be pathogenic (PMID: 21343334, 11920788, 2259385, 20128691, 1565143). This suggests that the glycine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change impairs the transactivation activity of the p53 protein in vitro (PMID: 12826609). This variant has been reported in an individual affected with childhood acute lymphoblastic leukemia, although it was not determined if this variant was a germline or somatic alteration (PMID: 21747090). ClinVar contains an entry for this variant (Variation ID: 376604). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 245 of the TP53 protein (p.Gly245Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.
Ambry Genetics	RCV001026295	SCV001188645	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The p.G245R pathogenic mutation (also known as c.733G>C), located in coding exon 6 of the TP53 gene, results from a G to C substitution at nucleotide position 733. The glycine at codon 245 is replaced by arginine, an amino acid with dissimilar properties. 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 (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 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). This mutation was observed in a family meeting Chompret criteria (Ambry internal data). In addition, other alterations at this position [p.G245D (c.734G>A) and p.G245S (c.733G>A)] have been reported in individuals with clinical histories suggestive of Li-Fraumeni syndrome (Srivastava S et al. Nature. 348(6303):747-9; Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Wong P et al. Gastroenterology. 2006 Jan;130:73-9; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13; Giacomazzi J et al. Cancer. 2013 Dec;119:4341-9; Jia Y et al. Cancer Biol. Ther. 2014 Aug;15:970-4; Churpek JE et al. Cancer. 2016 Jan 15;122(2):304-11). This variant is considered to be rare based on population 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV004022215	SCV004932393	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: 28166194, 27813088]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000432081	SCV000508247	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444128	SCV000508248	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424643	SCV000508249	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431462	SCV000508250	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444043	SCV000508251	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425790	SCV000508252	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436041	SCV000508253	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418277	SCV000508254	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426804	SCV000508255	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437043	SCV000508256	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419444	SCV000508257	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429713	SCV000508258	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441708	SCV000508259	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420527	SCV000508260	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430767	SCV000508261	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439119	SCV000508262	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only