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

Total submissions: 17

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	2020-06-21	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