ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.536A>G (p.His179Arg) (rs1057519991)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529132 SCV000629835 uncertain significance Li-Fraumeni syndrome 2020-03-12 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 Health, Inc RCV001023983 SCV001348246 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
GeneDx RCV001591055 SCV001826664 pathogenic not provided 2020-12-30 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: loss of growth suppression and transcriptional activation activities, with a dominant-negative effect observed (Flaman 1998, Ashur-Fabian 2007, Dearth 2007, Kotler 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a germline variant in individuals with breast or other cancer in published literature (Mandelker 2019, Kwong 2020); This variant is associated with the following publications: (PMID: 33138793, 30840781, 31050713, 22089350, 17311302, 16778209, 26619011, 29979965, 17361096, 15302922, 25148739, 16861262, 11297255, 20407015, 20182602, 26552420, 28315634, 9546439, 14559903, 12792784, 10567903, 17875924, 12726864, 22427690, 17646286, 10753186, 10519380, 15161705, 11051241, 18555592, 21113594, 21483000, 18689542, 25287991, 26230955, 25431194, 24446311, 9400993, 21190917, 20966976, 26585234, 2113594)
Database of Curated Mutations (DoCM) RCV000433943 SCV000508333 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443785 SCV000508334 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426502 SCV000508335 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438042 SCV000508336 likely pathogenic Carcinoma of gallbladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420789 SCV000508337 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427175 SCV000508338 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437826 SCV000508339 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000428674 SCV000508341 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438407 SCV000508342 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417695 SCV000508343 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429260 SCV000508344 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439947 SCV000508345 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421853 SCV000508346 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432550 SCV000508347 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440632 SCV000508348 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423292 SCV000508349 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433227 SCV000508350 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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,University Hospital Cologne RCV000785555 SCV000924127 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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