Submissions for variant NM_000251.3(MSH2):c.484G>A (p.Gly162Arg)

dbSNP: rs63750624

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076608	SCV000107644	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Invitae	RCV000524412	SCV000548190	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-09	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 162 of the MSH2 protein (p.Gly162Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with breast and prostate cancer, as well as individuals with clinicial features of Lynch syndrome (PMID: 12537652, 17101317, 18781619, 27606285, 28491141, 28874130, 29025352; Invitae). ClinVar contains an entry for this variant (Variation ID: 91105). 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: 17101317, 18781619, 18951462, 22949387, 24362816, 30998989). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491163	SCV000580414	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	The p.G162R pathogenic mutation (also known as c.484G>A), located in coding exon 3 of the MSH2 gene, results from a G to A substitution at nucleotide position 484. The glycine at codon 162 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been seen in several individuals who met Amsterdam I/II or Bethesda criteria for HNPCC (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). Several studies have shown this mutation to result in abnormal subcellular localization patterns, reduced MMR efficiency compared to the wild type, or was partially deleterious (Ollila S et al. Gastroenterology. 2006 Nov;131:1408-17; Kansikas M et al Hum. Mutat. 2011 Jan;32:107-15; Belvederesi L et al. Hum. Mutat. 2008 Nov;29:E296-309; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). This alteration has been classified as 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/]). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000662882	SCV000785789	pathogenic	Lynch syndrome 1	2017-11-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491163	SCV000905218	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 162 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 has defects in mismatch repair activity, protein expression/stability and sub-cellular localization (PMID: 18781619, 18951462) and tolerance to DNA-damaging agents (PMID: 30998989, 33357406). This variant has been reported in individuals affected with Lynch syndrome and Lynch syndrome-associated cancers (PMID: 12537652, 17101317, 18781619, 34667028, 36356413). Several of these individuals had tumors displaying microsatellite instability and/or mismatch repair protein loss in MSH2 via immunohistochemistry. 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 Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985811	SCV001134365	pathogenic	not provided	2019-01-25	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194033	SCV001363269	pathogenic	Hereditary nonpolyposis colon cancer	2019-10-29	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.484G>A (p.Gly162Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.484G>A has been reported in the literature in multiple individuals affected with colon cancer and HNPCC (Loader_2002, Ollila_2006, Belvederesi_2008, Thompson_2013, Brennan_2017, Rossi_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication, Ollila_2006, reports this variant had effects on protein stability, localization and DNA repair activity. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic
Sema4, Sema4	RCV000491163	SCV002534525	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662882	SCV004018373	pathogenic	Lynch syndrome 1	2023-03-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18951462, 17101317, 18781619]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Genetics and Molecular Pathology, SA Pathology	RCV000662882	SCV004175554	pathogenic	Lynch syndrome 1	2020-09-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004546430	SCV005042633	pathogenic	Muir-Torré syndrome		criteria provided, single submitter	clinical testing	The missense variant c.484G>Ap.Gly162Arg in MSH2 gene has been observed in heterozygous state in individuals with MSH2 related disorders Ponz et. al., 2018; Rossi et. al., 2017. Experimental studies have shown that this missense change affects MSH2 function Ollila et. al., 2008. The p.Gly162Arg variant is novel not in any individuals in 1000 Genomes and has allele frequency of 0.0004% in gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic by mutiple submitters. The amino acid change p.Gly162Arg in MSH2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 162 is changed to a Arg changing protein sequence and it might alter its composition and physicochemical properties. For these reasons, this variant has been classified as Pathogenic.