ClinVar Genomic variation as it relates to human health

PP3, PP4, PM2, PM3

Identified in the heterozygous state in patients with Lynch-related cancers or with a tumor demonstrating isolated loss of PMS2 expression via immunohistochemistry (Vaughn et al., 2010; Roberts et al., 2014; Wang et al., 2020); Published functional studies demonstrate a damaging effect: impaired MMR activity (Arora et al., 2017; D'Arcy et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25856668, 31391288, 24113346, 23012243, 31992580, 29345684, 20205264, 23729388, 28494185, 35189042, 18619468)

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35189042, 16873062, 18619468]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been observed homozygous in one or more individuals with Constitutional Mismatch Repair Deficiency Syndrome (CMMRD) [PMID: 23729388].

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMID: 23012243 (2013), 29345684 (2018), 31992580 (2020)), breast cancer (PMID: 24113346 (2014)), endometrial and ovarian cancer (PMID: 34357101 (2021)), and in other individuals tested for cancer predisposition (PMID: 20205264 (2010), 28514183 (2017)). The variant has also been reported in a homozygous individual affected with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 23729388 (2013)). Functional studies indicated the variant was moderately functional and showed a borderline deficiency in the DNA damage response affecting cell viability (PMID: 28494185 (2017)). 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 likely pathogenic.

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 699 of the PMS2 protein (p.Asp699His). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individuals with clinical features of Lynch syndrome or autosomal recessive constitutional mismatch repair deficiency (PMID: 20205264, 23012243, 23729388, 28514183; Invitae). ClinVar contains an entry for this variant (Variation ID: 140847). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PMS2 function (PMID: 28494185). 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.

The p.D699H pathogenic variant (also known as c.2095G>C), located in coding exon 12 of the PMS2 gene, results from a G to C substitution at nucleotide position 2095. The aspartic acid at codon 699 is replaced by histidine, an amino acid with similar properties. This alteration was identified in several individuals whose family history met Amsterdam criteria (Ambry internal data). This variant has also been identified in a probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or isolated loss of PMS2 expression by immunohistochemistry (IHC) (Ambry internal data). This alteration was also reported homozygous in a child with features suggestive of constitutional mismatch repair deficiency (CMMR-D); however, no tumor testing was performed (Walter AW et al. Pediatr Blood Cancer. 2013 Nov; 60(11):E135-6). In vitro studies have shown that the p.D699H variant exhibits expression levels similar to wildtype; however, protein function was reduced (Arora S et al. Cancer Biol. Ther. 2017 Jul;18:519-533). This variant was also identified in a patient diagnosed with colorectal as well as uterine cancers and microsatellite instability was detected along with isolated loss of PMS2 expression, but the tumor type was not specified (Bouras A et al. Genes Chromosomes Cancer, 2024 Jan;63:e23193). In another functional study, this variant showed reduced mismatch repair activity compared to wild type PMS2 (D'Arcy BM et al. Mol Genet Genomic Med, 2022 Feb;10:e1908). Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau E et al. Nat. Struct. Mol. Biol. 2013 Apr; 20(4):461-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). 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 variant is interpreted as a disease-causing mutation.

Variant summary: PMS2 c.2095G>C (p.Asp699His) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 221718 control chromosomes. c.2095G>C has been reported in the literature, including one patient whose tumors showed isolated loss of PMS2 by immunohistochemistry (Vaughn_2010), and in a child with constitutional mismatch repair deficiency who carried the variant in the homozygous state (Walter_2013). It has also been reported as a class 3 variant in an individual with MSI-high colorectal cancer and equivocal IHC analysis who underwent a comprehensive PMS2 analysis (example, Wang_2020). In addition, the variant has been reported in other patients being tested by various NGS cancer panels, without long-range PCR to confirm lack of pseudogene interference (Espenschied_2017, Goodenberger_2015, Mauer_2013, Roberts_2018, Li_2019). An in vitro functional study showed the variant to have proficient RNA expression and protein expression, with reduced viability leading authors to described the variant as moderately functional (Arora_2017). Another functional study demonstrated reduced mismatch repair capacity (MMR) as compared to wild-type (D'Arcy_2022). The following publications have been ascertained in the context of this evaluation (PMID: 28494185, 35189042, 28514183, 25856668, 31391288, 24113346, 29345684, 20205264, 23729388, 31992580). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The PMS2 c.2095G>C variant is predicted to result in the amino acid substitution p.Asp699His. This variant has been reported in individuals with Lynch syndrome related cancers (Vaughn et al. 2010. PubMed ID: 20205264; Vaughn et al. 2013. PubMed ID: 23012243), and observed in the homozygous state in a patient with constitutional mismatch repair deficiency (Walter et al. 2013. PubMed ID: 23729388). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic or pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140847/). This variant is interpreted as likely pathogenic.