Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| All of Us Research Program, |
RCV000529132 | SCV005425731 | likely pathogenic | Li-Fraumeni syndrome | 2023-04-28 | 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. |
| Myriad Genetics, |
RCV004022216 | SCV004931753 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-14 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 12726864, 22427690, 27557517]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| Ce |
RCV001591055 | SCV004010557 | pathogenic | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | TP53: PM1, PM2, PP4:Moderate, PS3:Moderate, PS4:Moderate |
| Gene |
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) |
| Color Diagnostics, |
RCV001023983 | SCV001348246 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-07-18 | 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. Functional studies have shown that this variant is partially functional in yeast transactivation assays, non-functional in human cell proliferation and growth suppression assays (PMID: 9627118, 12826609, 29979965, 30224644). This variant has been reported in individuals meeting Li-Fraumeni Chompret criteria and affected with adrenocortical carcinoma, osteosarcoma, choroid plexus carcinoma, and early onset breast cancer (PMID: 25148739, 33138793, PMC9164685, 35820297, IARC) and has been observed in numerous tumors at cancerhotspots.org. Other variants at this codon have been determined to be disease causing (ClinVar Variation ID: 406578, 127815, 376607). 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. |
| 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. |
| Labcorp Genetics |
RCV000529132 | SCV000629835 | uncertain significance | Li-Fraumeni syndrome | 2024-11-16 | 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). Invitae Evidence Modeling incorporating data from in vitro 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 (internal data). 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. |
| Prevention |
RCV003983035 | SCV004800571 | likely pathogenic | TP53-related disorder | 2024-07-03 | no assertion criteria provided | 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 et al. 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 pathogenic or likely pathogenic by the majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/376606/). In summary, this variant is interpreted as likely pathogenic. |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785555 | SCV000924127 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |