ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.733G>C (p.Gly245Arg) (rs28934575)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 18
Download table as spreadsheet
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 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. This variant is not present in population databases (ExAC no frequency). 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). Experimental studies have shown that this missense change impairs the transactivation activity of the p53 protein in vitro (PMID: 12826609). 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. 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.
Ambry Genetics RCV001026295 SCV001188645 pathogenic Hereditary cancer-predisposing syndrome 2019-05-10 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 Adenocarcinoma of stomach 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 Adenocarcinoma of prostate 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.