Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000529132 | SCV000629835 | uncertain significance | Li-Fraumeni syndrome | 2019-11-16 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with arginine at codon 179 of the TP53 protein (p.His179Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with chronic lymphocytic leukemia (PMID: 2113594). ClinVar contains an entry for this variant (Variation ID: 376606). Experimental studies have shown that this missense change disrupts TP53 protein function (PMID: 17311302, 22427690, 26585234, 16778209). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV001023983 | SCV001185932 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-23 | criteria provided, single submitter | clinical testing | The p.H179R variant (also known as c.536A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 536. The histidine at codon 179 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). It has been reported as a somatic mutation 174 times in various tumors, and as a germline mutation in a proband meeting Chompret criteria by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9). Numerous functional studies in yeast cells have demonstrated this alteration is deficient in transactivation activity and exhibits a dominant negative effect (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Hassan NM et al. Cancer Lett. 2008 Oct; 270(1):108-19). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). Functional studies in mammalian cells have shown gain of function activities for p.H179R, including interference with the p73 apoptotic pathway and the TGF-B tumor supressor signaling pathway (Kalo E et al. Mol. Cell. Biol. 2007 Dec; 27(23):8228-42; Bergamaschi D et al. Cancer Cell 2003 Apr; 3(4):387-402). In addition, another alteration at this same position, p.H179Q was identified as a de novo mutation in a patient with two Li-Fraumeni core cancers (Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Color | RCV001023983 | SCV001348246 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-08-22 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000433943 | SCV000508333 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443785 | SCV000508334 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426502 | SCV000508335 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438042 | SCV000508336 | likely pathogenic | Carcinoma of gallbladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420789 | SCV000508337 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427175 | SCV000508338 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437826 | SCV000508339 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417973 | SCV000508340 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428674 | SCV000508341 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438407 | SCV000508342 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417695 | SCV000508343 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429260 | SCV000508344 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439947 | SCV000508345 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421853 | SCV000508346 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432550 | SCV000508347 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440632 | SCV000508348 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423292 | SCV000508349 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433227 | SCV000508350 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445268 | SCV000508351 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785555 | SCV000924127 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |