Submissions for variant NM_000251.3(MSH2):c.118G>A (p.Gly40Ser)

gnomAD frequency: 0.00001  dbSNP: rs63751260

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627704	SCV000284097	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000236371	SCV000293503	uncertain significance	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in patients with colorectal cancer, polyps, or other cancer, including some individuals whose tumors demonstrate microsatellite instability and/or absent MSH2 protein staining (Yamada et al., 2003; Yamada et al., 2010; Kochi et al., 2015; Kiyozumi et al., 2019; Terashima et al., 2019; Hata et al., 2021; Takao et al., 2021); This variant is associated with the following publications: (PMID: 12792735, 26380806, 18383312, 32566746, 18822302, 21120944, 20043121, 31386297, 31666926, 34106356, 34755017)
Ambry Genetics	RCV000491838	SCV000580530	likely benign	Hereditary cancer-predisposing syndrome	2018-10-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000491838	SCV000684914	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 40 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 12792735, 26380806), bile duct cancer (PMID: 31666926), and unspecified cancer (PMID: 31386297). This variant has been identified in 2/227630 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781559	SCV000919699	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.118G>A (p.Gly40Ser) results in a non-conservative amino acid change located in the N-terminal domain (IPR007695) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-06 in 227630 control chromosomes (gnomAD). In addition, the variant was reported in Japanese healthy controls at a frequency of 0.0041 (jMorp; PMID: 29069501). The observed variant frequency within the Japanese subpopulation is about 7 times higher than the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), suggesting a benign role for the variant. c.118G>A has been reported in the literature in several individuals of Japanese ancestry, who were affected with colorectal cancer and other (unspecified) tumor phenotypes (example, Yamada_2010, Kochi_2015, Kiyozumi_2019, Terashima_2019), however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (MSH6 c.3980_3983dupATCA, p.Leu1200fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030704	SCV001193626	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004528275	SCV004106621	uncertain significance	MSH2-related disorder	2023-03-27	criteria provided, single submitter	clinical testing	The MSH2 c.118G>A variant is predicted to result in the amino acid substitution p.Gly40Ser. This variant has been reported in individuals with colorectal cancer or Lynch syndrome and Lynch syndrome associated cancers (Table S1, Kiyozumi et al. 2019. PubMed ID: 31386297; Table S1, Terashima et al. 2019. PubMed ID: 31666926; Yamada et al. 2003. PubMed ID: 12792735; Table S1, Takao et al. 2021. PubMed ID: 34106356). This variant is reported in 0.012% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47630448-G-A) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/90560/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003466962	SCV004196335	uncertain significance	Lynch syndrome 1	2023-07-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997143	SCV004828914	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 40 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with colorectal cancer (PMID: 12792735, 26380806), bile duct cancer (PMID: 31666926), and unspecified cancer (PMID: 31386297). This variant has been identified in 2/227630 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.