Submissions for variant NM_000546.6(TP53):c.734G>T (p.Gly245Val)

dbSNP: rs121912656

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000558455	SCV000629863	pathogenic	Li-Fraumeni syndrome	2021-07-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. 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). 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). This variant is present in population databases (rs121912656, ExAC 0.01%). 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.
Ambry Genetics	RCV001026313	SCV001188669	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-21	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. 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.
GeneDx	RCV001548147	SCV001768007	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a dominant-negative effect, lack of transcriptional activation, and loss of growth suppression activity (Kato 2003, Monti 2011, Kotler 2018); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26619011, 17606709, 21343334, 12826609, 18628487, 29625052, 11180592, 30720243, 30840781, 15510160, 11920788, 29979965)
Genome-Nilou Lab	RCV001026313	SCV002582465	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289525	SCV002583126	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476008	SCV004204284	pathogenic	Adrenocortical carcinoma, hereditary	2022-02-08	criteria provided, single submitter	clinical testing
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	Gastric adenocarcinoma	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	Prostate adenocarcinoma	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