Total submissions: 17
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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 |
RCV000419371 | SCV000508134 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429659 | SCV000508135 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440742 | SCV000508136 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423079 | SCV000508137 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428997 | SCV000508138 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439239 | SCV000508139 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422456 | SCV000508140 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000444195 | SCV000508142 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421269 | SCV000508143 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431939 | SCV000508144 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444224 | SCV000508145 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000785537 | SCV000924109 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |