Submissions for variant NM_000546.5(TP53):c.734G>A (p.Gly245Asp) (rs121912656)

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164465	SCV000215109	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-07	criteria provided, single submitter	clinical testing	The p.G245D mutation (also known as c.734G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 734. The glycine at codon 245 is replaced by aspartic acid, an amino acid with similar properties. This mutation was initially described in a classic Li-Fraumeni syndrome (LFS) family in which the mutation segregated with disease (Srivastava S et al. Nature. 348(6303):747-9). This alteration has been reported as a somatic mutation 162 times in various tumors and as a germline mutation 8 times by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). It is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, a dominant negative effect in yeast-based assays, decreased DNA binding activity to several responsive elements, and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Clin Cancer Res. 2007 Jul 1;13(13):3789-95; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205; Monti P et al. Mol Cancer Res. 2011 Mar; 9(3):271-9). 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 available evidence, p.G245D is classified as a pathogenic mutation.
Invitae	RCV000206683	SCV000261202	pathogenic	Li-Fraumeni syndrome	2020-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with aspartic acid at codon 245 of the TP53 protein (p.Gly245Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Li Fraumeni syndrome-associated cancers in a single family (PMID: 2259385) and also has been reported in individuals affected with chronic lymphocytic leukemia and chronic-phase primary myelofibrosis (PMID: 21232794, 22052707). ClinVar contains an entry for this variant (Variation ID: 12355). Experimental studies have shown that this missense change severely affects the functional activity of the p53 protein, abolishing its DNA-binding and transcriptional transactivation activities. This variant is classified as a severe deficiency allele with possible dominant-negative inhibitory effects (PMID: 17606709, 20128691, 12826609, 25119136). In addition, a different missense substitution at this codon (p.Gly245Ser) has been determined to be pathogenic (PMID: 12826609, 12885464, 7783166, 1565143, 1591732, 23538418). This suggests 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986053	SCV001134876	likely pathogenic	not provided	2019-03-26	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease.
GeneDx	RCV000986053	SCV001777843	pathogenic	not provided	2019-07-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31105275, 30482293, 30840781, 30720243, 29752319, 29979965, 8586466, 8794843, 27346245, 24763289, 25980754, 16861262, 9667734, 24651012, 22803791, 8633021, 23965983, 23967324, 26066407, 25860607, 2259385, 23531339, 24449472, 27323394, 17606709, 12826609, 21232794, 24590827, 26900293, 27696251, 17764544, 18656689, 22052707, 25634208, 25119136, 21343334, 20128691)
OMIM	RCV000013149	SCV000033396	pathogenic	Li-Fraumeni syndrome 1	1990-12-20	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440814	SCV000508199	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421831	SCV000508200	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429017	SCV000508201	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439739	SCV000508202	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422520	SCV000508203	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431450	SCV000508204	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444212	SCV000508205	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421349	SCV000508206	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432021	SCV000508207	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444304	SCV000508208	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427250	SCV000508209	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437916	SCV000508210	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443515	SCV000508211	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426192	SCV000508212	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436871	SCV000508213	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419718	SCV000508214	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785472	SCV000924044	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research