Submissions for variant NM_000251.3(MSH2):c.2047G>A (p.Gly683Arg)

gnomAD frequency: 0.00001  dbSNP: rs267607995

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076370	SCV000107397	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000132039	SCV000187098	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	clinical testing	The p.G683R pathogenic mutation (also known as c.2047G>A), located in coding exon 13 of the MSH2 gene, results from a G to A substitution at nucleotide position 2047. The glycine at codon 683 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in multiple HNPCC/Lynch syndrome probands whose tumors demonstrated microsatellite instability (MSI-H) and/or absence of MSH2 staining on immunohistochemistry (IHC) (Samowitz WS et al. Gastroenterology 2001 Oct;121(4):830-8; Sheng JQ et al. Cytogenet. Genome Res. 2008 Oct;122:22-27; Jasperson KW et al. Fam. Cancer 2010 Jun;9:99-107; Ambry internal data). In vitro functional analysis of p.G683R showed a significant reduction in mismatch repair activity compared to wildtype MSH2 (Drost M et al. Proc. Natl. Acad. Sci. U.S.A. 2013 Jun;110:9403-8; Nielsen SV et al. PLoS Genet. 2017 Apr;13:e1006739). This alteration has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000524373	SCV000253804	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 683 of the MSH2 protein (p.Gly683Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MSH2-related conditions (PMID: 11606497, 18931482, 19731080, 26248088; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90868). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 23690608). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264415	SCV001442546	pathogenic	Hereditary nonpolyposis colon cancer	2020-10-15	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2047G>A (p.Gly683Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes. c.2047G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Sheng_2008, Samowitz_2001, Coolbaugh-Murphy_2010, Jasperson_2010). Experimental studies have shown the variant to result in deficient repair activity in in vitro MMR complementation assay (Drost_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001588897	SCV001822908	pathogenic	not provided	2023-05-08	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; Observed in individuals with endometrial or colorectal cancer, with studied tumors demonstrating microsatellite instability (MSI) or absence of MSH2 expression on immunohistochemistry referred for genetic testing at GeneDx and in published literature (Samowitz et al., 2001; Sheng et al., 2008; Coolbaugh-Murphy et al., 2010; Jasperson et al., 2010; Guindalini et al., 2015); Published functional studies demonstrate a damaging effect: increased mutation rate, impaired interaction with MSH6, and mismatch repair (MMR) deficiency when compared to controls (Drost et al., 2013; Nielsen et al., 2017); This variant is associated with the following publications: (PMID: 20052760, 18931482, 22290698, 23760103, 11606497, 26552419, 26248088, 24362816, 26078562, 19062740, 28422960, 25980754, 18383312, 19731080, 18822302, 21120944, 23690608, 31615790, 31830689)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001588897	SCV002046196	pathogenic	not provided	2020-10-21	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in multiple individuals with Lynch syndrome and MSH2-associated cancers (PMID: 11606497 (2001), 18931482 (2008), 19731080 (2010), 26248088 (2015)). A functional study showed the variant caused significantly reduced DNA mismatch repair activity and MSH2 protein expression in vitro (PMID: 23690608 (2013)). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is located in a potentially critical protein domain. Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003452883	SCV004187983	pathogenic	Lynch syndrome 1	2023-08-07	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003452883	SCV004196931	pathogenic	Lynch syndrome 1	2021-10-11	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202225	SCV000257166	uncertain significance	not specified		no assertion criteria provided	research