ClinVar Miner

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

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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 RCV000490901 SCV000580482 pathogenic Hereditary cancer-predisposing syndrome 2019-05-14 criteria provided, single submitter clinical testing The p.G692R variant (also known as c.2074G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2074. The glycine at codon 692 is replaced by arginine, an amino acid with dissimilar properties. A similar mutation, c.2074G>C, which leads to the same amino acid change, p.G692R, has been reported in a Portuguese family meeting Amsterdam I criteria (Isidro G et al. Hum Mut. 2000 Jan;15(1):116). The glycine at position 692 is in a well conserved region, close to the ATP binding domain and functional analysis of the yeast equivalent demonstrated 5% steady-state levels of wildtype 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 AE et al. Genetics. 2007 Oct;177(2): 707-21). In addition, the c.2074G>C alteration has been classified as a likely pathogenic variant by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at []). Furthermore, all internal cases with the c.2074G>C mutation meet Bethesda or Amsterdam criteria and cases for which tumor studies were available showed concordance (Ambry Internal Data). The c.2074G>A variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the available evidence, this variant is classified as a pathogenic mutation.
Color Health, Inc RCV000490901 SCV000910480 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). A functional study has shown that this variant disrupts DNA mismatch repair activity in a mouse embryonic stem cell-based assay (PMID: 26951660). While to our knowledge, this specific variant has not been reported in individuals affected with hereditary cancer in the literature, a different variant (c.2074G>C) resulting in the same amino acid change has been reported in individuals affected with Lynch syndrome-associated cancers (PMID: 10612836) and is considered to be disease-causing (ClinVar variation ID: 90878). 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 RCV001378609 SCV001576212 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-05-26 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 missense change 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: 428477). This missense change has been reported to affect MSH2 protein function (PMID: 26951660, 17720936). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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