ClinVar Genomic variation as it relates to human health

The NM_000546.6: c.641A>G variant in TP53 is a missense variant predicted to cause substitution of histidine by arginine at amino acid 214 (p.His214Arg). This variant has been reported in 2 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 20522432; Internal lab contributor: SCV000581129.5). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000581129.5). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant has 35 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PM1. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024)

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

The p.H214R pathogenic mutation (also known as c.641A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 641. The histidine at codon 214 is replaced by arginine, an amino acid with highly similar properties. This variant was detected in an individual meeting Chompret criteria with breast cancer at 35, brain cancer at 40, and adrenocortical carcinoma at 41 (Ruijs MW et al. J. Med. Genet. 2010 Jun; 47(6):421-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Yamamoto S et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):181-9; Flaman JM et al. Oncogene 1998 Mar; 16(10):1369-72). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved through mammals on sequence alignment. 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.

The TP53 c.641A>G (p.His214Arg) variant has been reported in the published literature in an affected individual with Li-Fraumeni syndrome (PMID: 20522432 (2010)). Human cell line and yeast based functional assays demonstrated that this variant is damaging to protein function (PMIDs: 9546439 (1998), 10761705 (2000), 11920959 (2002), 12826609 (2003), and 30224644 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 214 of the TP53 protein (p.His214Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 20522432; external communication). ClinVar contains an entry for this variant (Variation ID: 376615). 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: 7732013, 9546439, 10761705, 11920959, 12826609, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9546439, 14559903, 25916844, 23967324, 21232794, 26053092, 23772609, 29707145, 9290701, 25584008, 10761705, 7732013, 26682952, 24523142, 19020536, 26331835, 18689542, 26066407, 28137276, 23196062, 26425688, 20436704, 25710373, 21197471, 16337994, 11920959, 24510342, 8242631, 24651012, 20407015, 29979965, 31394872, 30224644, 30840781, 27050224, 12826609, 29070607, 26619011, 24810334, 15510160, 31105275, 30720243, 34273903, 34887416, 36168441, 20522432, 35033608, 31881331, 33300245, 31533767, 37377684)

A heterozygous missense variant in exon 6 of the TP53 gene (chr17:g.7674890T>C; Depth: 180x) that results in the amino acid substitution of Arginine for Histidine at codon 214 (p.His214Arg; ENST00000269305.9) was detected. The p.His214Arg variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 and damging by SIFT, LRT, Mutation Taster2 tools. The reference codon is conserved in species. The Alternate allele depth of this TP53 variant is low [16.1%]. This could be due to germline mosaicism which has been reported for TP53 variants.

This missense variant replaces histidine with arginine at codon 214 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 results in protein that is non-functional in yeast transactivation assays (PMID: 12826609, 20407015), human cell growth suppression assays (PMID: 30224644), and human cell proliferation assay (PMID: 29979965). This variant has been reported in a 41 year old Dutch individual affected with Li Fraumeni-like syndrome meeting Chompret criteria (PMID: 20522432) and a 3 year old Chinese individual affected with glioma (PMID: 35033608). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.