ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2074G>C (p.Gly692Arg) (rs63750232)

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Total submissions: 4
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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 []). 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 Health, Inc 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 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 692 of the MSH2 protein (p.Gly692Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 28577310), and to segregate with Lynch syndrome in a single family (PMID: 10612836). ClinVar contains an entry for this variant (Variation ID: 90878). This variant has been reported to affect MSH2 protein function (PMID: 26951660, 17720936). This variant disrupts the p.Gly692 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 29212164, 23454724, 12624141, 28135145, 23729658), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.

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