Submissions for variant NM_000251.3(MSH2):c.1862G>C (p.Arg621Pro)

dbSNP: rs759263820

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567575	SCV000669850	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-04	criteria provided, single submitter	clinical testing	The p.R621P variant (also known as c.1862G>C), located in coding exon 12 of the MSH2 gene, results from a G to C substitution at nucleotide position 1862. The arginine at codon 621 is replaced by proline, an amino acid with dissimilar properties. This variant has been identified in multiple probands whose Lynch syndrome-associated tumors demonstrated loss of MSH2 and MSH6 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Ambry internal data). The yeast equivalent of this variant demonstrated an increased mutation rate in a multiplexed functional assay performed using Saccharomyces cerevisiae (Ollodart AR et al. Genetics, 2021 Jun;218:). 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 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	RCV000806694	SCV000946707	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 621 of the MSH2 protein (p.Arg621Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (internal data). ClinVar contains an entry for this variant (Variation ID: 483736). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. This variant disrupts the p.Arg621 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21520333, 30702970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
GeneDx	RCV004767402	SCV005376480	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004767402	SCV005623634	pathogenic	not provided	2024-12-05	criteria provided, single submitter	clinical testing	The MSH2 c.1862G>C (p.Arg621Pro) variant has been reported in the published literature in functional studies that demonstrate this variant is damaging to mismatch repair function (PMID: 33848333 (2021), 33357406 (2021)). This variant has been reported in an individual with colorectal cancer (Invitae, personal communication regarding ClinVar ID: 483736). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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.