Submissions for variant NM_000546.6(TP53):c.536A>G (p.His179Arg)

gnomAD frequency: 0.00001  dbSNP: rs1057519991

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000529132	SCV000629835	uncertain significance	Li-Fraumeni syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 179 of the TP53 protein (p.His179Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic lymphocytic leukemia (PMID: 21113594). ClinVar contains an entry for this variant (Variation ID: 376606). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 16778209, 17311302, 22427690, 26585234, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	2023-02-01	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 has been reported as a somatic mutation 174 times in various tumors by the IARC TP53 database, and as a germline mutation in probands meeting Chompret criteria (Ambry internal data; Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9). 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). 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). 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 Diagnostics, LLC DBA Color Health	RCV001023983	SCV001348246	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 179 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant is partially functional in yeast transactivation assays, non-functional in human cell proliferation assays, and exhibits dominant-negative effect and loss of function in human cell growth suppression assays (PMID: 12826609, 16778209, 17311302, 22427690, 26585234, 30224644, 32980694). This variant has been reported in individuals affected with early-onset breast cancer meeting Chompret criteria (PMID: 33138793, 35820297; IARC Database) and in an individual affected with choroid plexus carcinoma (PMCID: PMC9164685). Two different missense variants at the same amino acid positions, H179Q and H179Y, are established pathogenic variants (ClinVar variation ID 127815, 376607, 406578). This variant has been identified in 1/251340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx	RCV001591055	SCV001826664	pathogenic	not provided	2022-12-23	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 et al., 1998; Ashur-Fabian et al., 2007; Dearth et al., 2007; Kotler et al., 2018; Giacomelli et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26585234, 10753186, 22427690, 15161705, 28315634, 12726864, 2113594, 21190917, 20966976, 9400993, 18689542, 24446311, 25431194, 26230955, 25287991, 21483000, 21113594, 18555592, 11051241, 10519380, 17646286, 17875924, 10567903, 12792784, 14559903, 9546439, 16861262, 26552420, 20182602, 20407015, 11297255, 25148739, 17361096, 26619011, 16778209, 17311302, 22089350, 31050713, 30840781, 15302922, 29979965, 15510160, 32817165, 30224644, 33138793)
CeGaT Center for Human Genetics Tuebingen	RCV001591055	SCV004010557	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	TP53: PM1, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate
PreventionGenetics, part of Exact Sciences	RCV003983035	SCV004800571	likely pathogenic	TP53-related condition	2024-02-19	criteria provided, single submitter	clinical testing	The TP53 c.536A>G variant is predicted to result in the amino acid substitution p.His179Arg. This variant has been reported multiple times as a somatic variant, but it has also been detected in the germline of individuals with breast cancer and unspecified cancers (Supplementary Table 4, Mandelker et al 2019. PubMed ID: 31050713; Kwong et al. 2020. PubMed ID: 33138793; Dong et al. 2011. PubMed ID: 21113594). It has also been detected in a control individual (Okawa et al. 2023. PubMed ID: 36243179). In vitro functional studies suggest this variant impacts protein function (see, for example, Kalo et al. 2007. PMID: 17875924; Hassan et al. 2008. PubMed ID: 18555592; Giacomelli et al. 2018 PubMed ID: 30224644). Alternative nucleotide substitutions affecting the same amino acid (p.His179Asp, p.His179Tyr, p.His179Gln) have been reported in individuals with breast cancer or Li-Fraumeni syndrome (Renaux-Petel et al. 2018. PubMed ID: 29070607; Brehin et al. 2018. PubMed ID: 28477316; Gonzalez. 2009. PubMed ID: 19556618). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic by vast majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/376606/). In summary, this variant is interpreted as likely pathogenic.
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	Gallbladder carcinoma	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	Gastric adenocarcinoma	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, University Hospital Cologne	RCV000785555	SCV000924127	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research