Submissions for variant NM_000251.3(MSH2):c.304G>A (p.Val102Ile)

gnomAD frequency: 0.00002  dbSNP: rs193922373

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030251	SCV000107592	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability 0.001-0.049
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236541	SCV000052918	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.304G>A (p.Val102Ile) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, 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 2.4e-05 in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.304G>A has been reported in the literature in individuals affected with or fulfilling the Amsterdam I (Ward_2002) or revised Bethesda criteria (Chao_2008) for Lynch syndrome. Furthermore, a tumor specimen with this variant showed positive expression of MLH1 and MSH2 with MSI stable pattern (Ward_2002).These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (MSH2 c.1216C>T, p.Arg406*), 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 (VUS, n=4; likely benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000130254	SCV000185098	likely benign	Hereditary cancer-predisposing syndrome	2021-08-17	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.
GeneDx	RCV000657039	SCV000292988	likely benign	not provided	2020-12-02	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22290698, 17192056, 12200596, 26951660, 32926152)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236541	SCV000539683	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: LB by expert panel
Invitae	RCV000536977	SCV000625414	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000662359	SCV000784742	likely benign	Lynch syndrome 1	2017-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130254	SCV000904003	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 102 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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), or in mouse embryonic stem cells (PMID: 26951660). This variant has been reported in an individual affected with colorectal cancer whose family history fulfilled Amsterdam I criteria (PMID: 12200596). This variant has been identified in 6/251296 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.
Myriad Genetics, Inc.	RCV000662359	SCV004018431	likely benign	Lynch syndrome 1	2023-03-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004532423	SCV004739966	likely benign	MSH2-related disorder	2023-10-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV000030251	SCV004824340	uncertain significance	Lynch syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 102 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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), or in mouse embryonic stem cells (PMID: 26951660). This variant has been reported in an individual affected with colorectal cancer whose family history fulfilled Amsterdam I criteria (PMID: 12200596), however, the tumor showed microsatellite stability and intact MSH2 protein via immunohistochemistry. This variant has been identified in 6/251296 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.