ClinVar Genomic variation as it relates to human health

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 33357406].

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro622 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7717919, 8261515, 17720936, 21309037, 22102614, 26951660). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 33357406). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 622 of the MSH2 protein (p.Pro622Arg). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 265573). This missense change has been observed in individuals with Lynch syndrome (PMID: 21520333; externalcommunication).

The p.P622R variant (also known as c.1865C>G), located in coding exon 12 of the MSH2 gene, results from a C to G substitution at nucleotide position 1865. The proline at codon 622 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in an individual with clinical features of Lynch syndrome (Ambry internal data). This alteration was also identified as somatic in an endometrial tumor that displayed high microsatellite instability (MSI-H) with loss of MSH2 as well as MSH6 on immunohistochemistry (IHC) and a germline likely pathogenic variant in MSH2 was determined to be in trans (Ambry internal data). A pathogenic mutation (p.P622L) at the same codon has been reported to segregate with disease in families that met Amsterdam I/II criteria for Lynch syndrome and results from tumor testing for these individuals showed absent MSH2/MSH6 on IHC and/or MSI-H (Leach FS et al. Cell 1993 Dec;75:1215-25; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat., 2009 May;30:757-70). Also, numerous studies in mammalian and yeast systems have demonstrated that p.P622L results in reduced mismatch repair activity (Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Observed in a family reported to have Lynch syndrome (PMID: 28874130); Published functional studies suggest a damaging effect: resistance to 6-TG similar to known pathogenic variants (PMID: 33357406); 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: 18822302, 21120944, 36550560, 28874130, 33357406)

The MSH2 c.1865C>G (p.Pro622Arg) variant has been reported in the published literature in a family with Lynch syndrome (PMID: 28874130 (2017)). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 33357406 (2021)). 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.