ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.731G>A (p.Gly244Asp) (rs985033810)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413969 SCV000491278 likely pathogenic not provided 2016-06-27 criteria provided, single submitter clinical testing This variant was observed in at least one family who fulfills clinical diagnostic criteria for Li Fraumeni syndrome (Achatz 2007). Multiple transactivation assays demonstrate significant loss of TP53 function (Brachmann 1998, Dearth 2007, Monti 2011). Yeast based assays have shown TP53 Gly244Asp to have a dominant negative effect on gene function (Brachmann 1996, Sakuragi 2005). TP53 Gly244Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly244Asp occurs at a position that is conserved across species and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider TP53 Gly244Asp to be a likely pathogenic variant.
Invitae RCV000477083 SCV000545270 pathogenic Li-Fraumeni syndrome 2019-07-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 244 of the TP53 protein (p.Gly244Asp). 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 in individuals affected with breast and/or ovarian cancer, colon cancer, and melanoma (PMID: 16494995, 29470806, Invitae). It also segregated with early-onset breast cancer in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 372785). Experimental studies have shown that this variant disrupts the transactivation activity of the p53 protein (PMID: 16494995, 16861262, 21343334, 22319594). A different missense substitution at this codon (p.Gly244Ser) has been determined to be pathogenic (PMID: 18511570, 26818906, 25925845, 18628487, 24307375). 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.
Ambry Genetics RCV000561866 SCV000667184 pathogenic Hereditary cancer-predisposing syndrome 2020-08-21 criteria provided, single submitter clinical testing The p.G244D pathogenic mutation (also known as c.731G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 731. The glycine at codon 244 is replaced by aspartic acid, an amino acid with similar properties. This variant has been detected in a Brazilian individual diagnosed with breast cancer at 40y and colorectal cancer (age unspecified) with a family history of early-onset bone cancer, breast cancer, sarcoma, and cancer of the female genital organs (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170:189-196). The p.G244D variant has also been reported in children with Li-Fraumeni syndrome-related cancers (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180. Grobner S et al. Nature. 2018 03;555(7696):321-327). The p.G244D variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays. (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science. 1994 Jul; 265(5170):346-55). In addition, two alterations at this same position (p.G244S and p.G244V) have been identified in individuals meeting Chompret criteria (Krutilkova V et al. Eur J Cancer. 2005 Jul;41(11):1597-603; Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Database of Curated Mutations (DoCM) RCV000419371 SCV000508134 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429659 SCV000508135 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440742 SCV000508136 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423079 SCV000508137 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428997 SCV000508138 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439239 SCV000508139 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422456 SCV000508140 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432739 SCV000508141 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444195 SCV000508142 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421269 SCV000508143 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431939 SCV000508144 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444224 SCV000508145 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427142 SCV000508146 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 RCV000785537 SCV000924109 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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