ClinVar Genomic variation as it relates to human health

The p.R169H variant (also known as c.506G>A), located in coding exon 5 of the PMS2 gene, results from a G to A substitution at nucleotide position 506. The arginine at codon 169 is replaced by histidine, an amino acid with highly similar properties. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as a variant of uncertain significance (Shirts BH et al. Am J Hum Genet. 2018 Jul 5;103(1):19-29). In an in vitro complementation assay, this variant had reduced mismatch repair activity compared to wild type PMS2 (Rayner E et al. Hum Mutat, 2022 Sep;43:1249-1258). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The PMS2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169His. This variant has been reported in a patient with Lynch syndrome (Okkels et al. 2019. PubMed ID: 31433215), an individual with breast cancer (Dong et al. 2018. PubMed ID: 30039884), and in a study of somatic mutations in tumors (Table S3, Shirts et al. 2018. PubMed ID: 29887214). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-6042115-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182811/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data].

This missense variant replaces arginine with histidine at codon 169 of the PMS2 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the PMS2 protein (p.Arg169His). This variant is present in population databases (rs730881917, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and clinical features of Lynch syndrome (PMID: 30039884, 31433215). ClinVar contains an entry for this variant (Variation ID: 182811). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 35451539). 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.

This missense variant replaces arginine with histidine at codon 169 of the PMS2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study analyzing somatic driver variants was inconclusive for this variant (PMID: 29887214). have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome (PMID: 31433215) and an individual affected with breast cancer (PMID: 30039884). This variant has been identified in 3/281050 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

PMS2 NM_000535.5:c.506G>A has a 60.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the PMS2 locus. See Shirts et al 2018, PMID 29887214.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: decreased MMR activity compared to wild type (PMID: 35451539); This variant is associated with the following publications: (PMID: 28912153, 30039884, 35451539, 11574484, 31433215, 34570441)