Submissions for variant NM_000251.3(MSH2):c.2074G>C (p.Gly692Arg)

dbSNP: rs63750232

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076380	SCV000107407	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics	RCV000491588	SCV000580386	pathogenic	Hereditary cancer-predisposing syndrome	2017-09-20	criteria provided, single submitter	clinical testing	The p.G692R pathogenic mutation (also known as c.2074G>C), located in coding exon 13 of the MSH2 gene, results from a G to C substitution at nucleotide position 2074. The glycine at codon 692 is replaced by arginine, an amino acid with dissimilar properties. In one study, this alteration was detected in the proband and two other affected members of a Portuguese Lynch/HNPCC syndrome family. The glycine at position 692 is in a well conserved region, close to the ATP binding domain (Isidro et al. Hum Mut. 2000 Jan; 15(1):116). Additionally, functional analysis of the yeast equivalent demonstrated 5% steady-state levels of MSH2 and a loss of interaction with all MSH2 partners. A variant was considered to have a significant defect if levels were <40% of wildtype MSH2 (Gammie et al. Genetics. 2007 Oct; 177(2): 707-21). Another study looked at site-directed mutagenesis in mouse embryonic stem cells (mESCs) and selected for MMR-deficient cell lines which were subsequently sequenced to confirm that these cell lines contained the mutation of interest. The abundance of MSH2 protein in mESCs with the G692R alteration was 4% relative to the wildtype mESCs (MSH6 levels were also noted to mirror the decrease in MSH2 levels in the variant cell line); additionally, cells with the G692R alteration were shown to be MSI-H (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). This amino acid position is highly conserved in available vertebrate species. This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000491588	SCV000908324	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-02	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 692 of the MSH2 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts DNA mismatch repair activity in yeast and mouse embryonic stem cell-based assays (PMID: 17720936, 26951660). This variant has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 10612836). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV000821619	SCV000962388	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-28	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 26951660). 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. ClinVar contains an entry for this variant (Variation ID: 90878). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 10612836, 28577310; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 692 of the MSH2 protein (p.Gly692Arg). This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12624141, 23454724, 23729658, 28135145, 29212164). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.