ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1829A>C (p.His610Pro)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002410486 SCV002711135 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-03 criteria provided, single submitter clinical testing The p.H610P variant (also known as c.1829A>C), located in coding exon 12 of the MSH2 gene, results from an A to C substitution at nucleotide position 1829. The histidine at codon 610 is replaced by proline, an amino acid with similar properties. This alteration has been identified in the germline of individuals whose Lynch syndrome associated tumors demonstrated high microsatellite instability (MSI-H) with absent MSH2/MSH6 expression on immunohistochemistry (IHC) and a somatic pathogenic MSH2 mutation was also identified in one of the cases (Ambry internal data; Okkels H et al. Genet Test Mol Biomarkers. 2019 Sep;23:688-695; Fokkema IF et al. Hum. Mutat. 2011 May;32:557-63). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Gupta S et al. Nat. Struct. Mol. Biol. 2011 Dec;19:72-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV003482411 SCV004228504 likely pathogenic Lynch syndrome 2023-12-15 criteria provided, single submitter clinical testing The following ACMG criteria is used: PM2_Supporting (not reported in gnomAD), PS3 (PMID: 33357406); PP4_Strong (lack of MSH2 ekspression/MSI in three tumors (one CRC and two endometrial) from three different families
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003493949 SCV004243565 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing

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