Submissions for variant NM_000535.7(PMS2):c.2531C>A (p.Pro844His)

dbSNP: rs587782787

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132336	SCV000187424	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing	The p.P844H variant (also known as c.2531C>A), located in coding exon 15 of the PMS2 gene, results from a C to A substitution at nucleotide position 2531. The proline at codon 844 is replaced by histidine, an amino acid with similar properties. This variant was reported in an individual that met Bethesda guidelines and was diagnosed at age 50 with microsatellite stable (MSS) colorectal cancer that demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Borras E et al. Cancer Prev Res (Phila), 2017 Oct;10:580-587). In a French cohort of 31 individuals with constitutional mismatch repair deficiency syndrome (CMMRD), this variant was reported as homozygous in an individual with a personal history of colorectal cancer/polyps at age 20, glioblastoma at age 32, and gastric carcinoma at age 32 (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8). Furthermore, tumor testing performed on this proband's glioma demonstrated loss of PMS2 expression on immunohistochemistry (IHC) with high microsatellite instability (MSI-H) and loss of PMS2 expression on IHC was also seen in non-neoplastic cells (Lavoine N et al. J. Med. Genet., 2015 Nov;52:770-8; Guerrini-Rousseau L et al. Neuro-Oncology Advances, 2019 Nov;1(1):1-13; doi:10.1093/noajnl/vdz033). This variant has been reported in conjunction with PMS2 p.R421*, in an individual with a personal history of colorectal cancer and four tubular adenomas diagnosed at age 27, and functional studies performed demonstrated <10% MMR activity (Shuen AY et al. J Clin Oncol, 2019 02;37:461-470). This variant has also been identified in individuals whose Lynch syndrome associated tumors demonstrated loss of PMS2 expression on IHC, two of which also had a second somatic pathogenic PMS2 mutation identified (Ambry internal data, internal correspondence). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469886	SCV000552031	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 844 of the PMS2 protein (p.Pro844His). 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 constitutional mismatch repair deficiency syndrome, Lynch syndrome (PMID: 26318770; internal data). ClinVar contains an entry for this variant (Variation ID: 142877). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PMS2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMS2 function (PMID: 35451539). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV002279947	SCV004187667	pathogenic	Lynch syndrome 4	2023-09-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35451539]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26318770, 33259954].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477560	SCV004218996	pathogenic	not provided	2023-04-26	criteria provided, single submitter	clinical testing	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 an individual homozygous for the variant and affected with constitutional mismatch repair deficiency syndrome (CMMRD) (PMID: 26318770 (2015)). Additionally, the variant has been reported in individuals with colorectal cancer (PMIDs: 30608896 (2019), 28765196 (2017)). Functional studies performed demonstrated reduced MMR activity (PMID: 30608896 (2019)). 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.
GeneDx	RCV003477560	SCV005201278	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (PMID: 30608896, 35451539); 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: 26318770, 33259954, 32642664, 35451539, 30608896, 28765196, Fukui2011[Chapter], 18619468)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055606	SCV005725802	likely pathogenic	Hereditary nonpolyposis colon cancer	2024-11-25	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2531C>A (p.Pro844His) results in a non-conservative amino acid change in 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 187528 control chromosomes (gnomAD). c.2531C>A has been reported in the literature in individuals affected with Constitutional mismatch repair deficiency (Lavoine_2015, Shuen_2019). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal mismatch repair activity (Rayner_2022). The following publications have been ascertained in the context of this evaluation (PMID: 26318770, 38552658, 35451539, 30608896). ClinVar contains an entry for this variant (Variation ID: 142877). Based on the evidence outlined above, the variant was classified as likely pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002279947	SCV002568087	likely pathogenic	Lynch syndrome 4	2021-02-22	no assertion criteria provided	clinical testing	An individual with a clinical phenotype consistent with constitutional mismatch repair deficiency was homozygous for PMS2 p.P844H (Lavoine 2015), which is most consistent with a pathogenic classification. The PMS2 p.P844H variant is rare in population databases (gnomad.broadinstitute.org).
PreventionGenetics, part of Exact Sciences	RCV003894999	SCV004717806	likely pathogenic	PMS2-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The PMS2 c.2531C>A variant is predicted to result in the amino acid substitution p.Pro844His. This variant has been reported in the homozygous and presumed compound heterozygous state in three individuals with constitutional mismatch repair deficiency syndrome (Table 1, Lavoine et al. 2015. PubMed ID: 26318770; Table A1, Shuen et al. 2019. PubMed ID: 30608896; Table 1, Guerrini-Rousseau et al. 2019. PubMed ID: 32642664). It has been reported in an individual with a personal and/or family history of Lynch syndrome (Tables S1 and S11, Borras et al. 2017. PubMed ID: 28765196). In vitro experimental studies suggest this variant impairs mismatch repair activity (Table 1, Rayner et al. 2022. PubMed ID: 35451539). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142877/). This variant is interpreted as likely pathogenic.