ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.734G>T (p.Gly245Val) (rs121912656)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000558455 SCV000629863 pathogenic Li-Fraumeni syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 245 of the TP53 protein (p.Gly245Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs121912656, ExAC 0.01%). This variant has been reported in the literature in individuals with lung cancer, follicular lymphoma, and Li-Fraumeni associated cancers (PMID: 11180592, 11920788, 18628487, 17606709, Invitae). ClinVar contains an entry for this variant (Variation ID: 376603). Experimental studies have shown that this missense change disrupts the ability of TP53 to bind to DNA and significantly decreases its transcriptional transactivation activity (PMID: 12826609, 17606709). Different missense substitutions at this codon (p.Gly245Asp and p.Gly245Ser) have been determined to be pathogenic (PMID: 1565143, 24122735, 17311302, 12826609,20128691, 21343334, 25119136, 2259385), further suggesting that the glycine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001026313 SCV001188669 pathogenic Hereditary cancer-predisposing syndrome 2019-10-03 criteria provided, single submitter clinical testing The p.G245V pathogenic mutation (also known as c.734G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 734. The glycine at codon 245 is replaced by valine, an amino acid with dissimilar properties.<span style="font-family:sans-serif,arial,verdana,trebuchet ms"> This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity as well as dominant negative effect 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; Waddell S et al. Oncogene, 2001 Sep;20:6001-8). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). Other disease-causing mutations, p.G245D and p.G245S, have been described in the same codon in numerous individuals with clinical histories meeting diagnostic criteria for 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). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Database of Curated Mutations (DoCM) RCV000430431 SCV000508215 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435854 SCV000508216 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418643 SCV000508217 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429303 SCV000508218 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439974 SCV000508219 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421020 SCV000508220 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428216 SCV000508221 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438982 SCV000508222 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421739 SCV000508223 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434145 SCV000508224 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444483 SCV000508225 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424123 SCV000508226 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434833 SCV000508227 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443716 SCV000508228 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426568 SCV000508229 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437258 SCV000508230 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only

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