Total submissions: 21
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 | 2020-01-08 | 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. |
OMIM | RCV000013149 | SCV000033396 | pathogenic | Li-Fraumeni syndrome 1 | 1990-12-20 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440814 | SCV000508199 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421831 | SCV000508200 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000439739 | SCV000508202 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422520 | SCV000508203 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431450 | SCV000508204 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444212 | SCV000508205 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421349 | SCV000508206 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432021 | SCV000508207 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444304 | SCV000508208 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427250 | SCV000508209 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437916 | SCV000508210 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443515 | SCV000508211 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426192 | SCV000508212 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436871 | SCV000508213 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000785472 | SCV000924044 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |