Submissions for variant NM_000546.6(TP53):c.734G>A (p.Gly245Asp)

dbSNP: rs121912656

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164465	SCV000215109	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-31	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 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). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). 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	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 245 of the TP53 protein (p.Gly245Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with chronic lymphocytic leukemia and chronic-phase primary myelofibrosis and Li Fraumeni syndrome-associated cancers (PMID: 2259385, 21232794, 22052707). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12355). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 25119136, 29979965). This variant disrupts the p.Gly245 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1591732, 7783166, 12826609, 12885464, 23538418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	2023-03-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, aberrant DNA binding, and dominant-negative effect (Kato et al., 2003; Dearth et al., 2007; Malcikova et al., 2010; Monti et al., 2011; Kotler et al., 2018); Not observed at 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: 21232794, 24590827, 27696251, 23531339, 23967324, 25980754, 20128691, 21343334, 25119136, 25634208, 22052707, 18656689, 17764544, 26900293, 12826609, 17606709, 27323394, 24449472, 25860607, 26066407, 23965983, 8633021, 22803791, 24651012, 9667734, 8794843, 16861262, 24763289, 8586466, 27346245, 29752319, 31105275, 30482293, 30840781, 30720243, 34949788, 29979965, 15510160, 30224644, 2259385)
Color Diagnostics, LLC DBA Color Health	RCV000164465	SCV002053062	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-02-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 245 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be non-functional in DNA binding assay (PMID: 20128691), transactivation assay (IARC database and PMID: 12826609, 21343334) and human cell proliferation assay (PMID: 29979965). This variant has been reported to segregate with disease in 4 individuals from a family affected with Li-Fraumeni syndrome (PMID: 2259385) and has been observed in an individual affected with early-onset and familial breast cancer meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 30482293). This variant has been identified in 1/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same amino acid position, p.Gly245Ser and p.Gly245Val, are known to be disease-causing (ClinVar variation ID: 12365, 376603), indicating that glycine at this position is important for TP53 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000164465	SCV002582362	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013149	SCV002583023	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473082	SCV004204266	pathogenic	Adrenocortical carcinoma, hereditary	2022-11-10	criteria provided, single submitter	clinical testing
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	Prostate adenocarcinoma	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	Gastric adenocarcinoma	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, University Hospital Cologne	RCV000785472	SCV000924044	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research