Submissions for variant NM_000251.3(MSH2):c.490G>A (p.Gly164Arg)

dbSNP: rs63750582

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076612	SCV000107648	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000491974	SCV000580413	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The p.G164R pathogenic mutation (also known as c.490G>A) is located in coding exon 3 of the MSH2 gene. This alteration results from a G to A substitution at nucleotide position 490. The glycine at codon 164 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been identified in multiple HNPCC/Lynch syndrome kindreds (Mangold et. al, Int J Cancer. 2005; 116(5): 692-702, Ou et al, Hum Mutat. 2007; 28(11): 1047-54, Lucci-Cordisco et. al., Cancer Biomarkers. 2006; 2:11-27). In addition, in an in vitro MMR assay, p.G164R demonstrated complete loss of MMR function (Ollila et al., Gastroent. 2006; 131: 1408). This alteration has been classified as pathogenic 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/]). This variant is considered to be rare based on population 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293544	SCV001482141	pathogenic	Hereditary nonpolyposis colon cancer	2021-02-09	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.490G>A (p.Gly164Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector 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 251486 control chromosomes. c.490G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Olila_2006, Mangold_2005, Yurgelun_2015). Experimental evidence shows the variant to result in complete loss of MMR function, with impact on protein stability (Ollila_2006, Olila_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001390798	SCV001592645	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2020-10-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly164 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 26648449, Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects MSH2 protein function (PMID: 17101317, 18951462). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MSH2 protein function. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 17101317, 15849733, Invitae). ClinVar contains an entry for this variant (Variation ID: 91109). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 164 of the MSH2 protein (p.Gly164Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine.
Myriad Genetics, Inc.	RCV003452944	SCV004186747	likely pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	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: 17101317, 26951660]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18951462].
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249918	SCV001423935	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing