ClinVar Miner

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

dbSNP: rs587782787
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Total submissions: 6
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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.
Invitae RCV000469886 SCV000552031 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-01-07 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; Invitae). ClinVar contains an entry for this variant (Variation ID: 142877). 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 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.
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.
PreventionGenetics, part of Exact Sciences RCV003894999 SCV004717806 likely pathogenic PMS2-related disorder 2023-11-30 criteria provided, single submitter 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.
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).

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