Submissions for variant NM_000251.3(MSH2):c.1790A>C (p.Asp597Ala)

gnomAD frequency: 0.00011  dbSNP: rs548407418

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162476	SCV000212849	likely benign	Hereditary cancer-predisposing syndrome	2021-07-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000167995	SCV000218645	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162476	SCV000292190	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 597 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). A functional study reported that this variant may not impact DNA mismatch repair activity based on a 6-thioguanine sensitivity assay in Msh2-deficient haploid human cells (PMID: 33357406). This variant has been reported in one individual affected with pediatric leukemia (PMID: 26580448), an individual affected with an unspecified Lynch syndrome-associated cancer (PMID: 31391288), and in a healthy control (PMID: 33471991). This variant has been identified in 4/251456 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.
Counsyl	RCV000409730	SCV000489409	uncertain significance	Lynch syndrome 1	2016-10-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000480972	SCV000566598	uncertain significance	not provided	2023-03-08	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 a pediatric patient with leukemia and in an individual whose tumor was assessed with MSI and/or IHC (Zhang et al., 2015; Li et al., 2020); Published functional studies suggest a neutral effect: demonstrates resistance to 6-TG similar to wild type (Jia et al., 2020); This variant is associated with the following publications: (PMID: 31569399, 33471991, 18822302, 9774676, 21120944, 26580448, 33357406, 31391288)
Mendelics	RCV000708834	SCV000837839	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480972	SCV000889426	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000087 (3/34586 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with Lynch syndrome-associated cancer and acute lymphoblastic leukemia (PMIDs: 31391288 (2020) and 26580448 (2015)). In a large case-control study, this variant has only been detected in an unaffected control but not in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). A screening assay based on cell survival in response to 6-thioguanine treatment indicated the variant has neutral effects on DNA mismatch repair function in vivo (PMID: 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000708834	SCV000890967	uncertain significance	Lynch syndrome	2020-09-23	criteria provided, single submitter	clinical testing	The MSH2 c.1790A>C (p.Asp597Ala) missense change has a maximum subpopulation frequency of 0.0087% gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/2-47702194-A-C). In silico tools are not in agreement about a tolerated or damaging effect on the gene or protein product and functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781560	SCV000919704	likely benign	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1790A>C (p.Asp597Ala) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 150914 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1790A>C has been reported in the literature in individuals affected with pediatric leukemia and Lynch syndrome-associated cancer (Zhang_2015, Li_2020), but was also found among healthy controls (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant restores 6-thioguanine sensitivity, thus likely does not impact DNA mismatch repair activity (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 26580448, 31569399, 31391288, 33357406, 33471991). Ten other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=8), likely benign (n=1) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000162476	SCV002534412	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000480972	SCV003808950	uncertain significance	not provided	2019-06-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409730	SCV004018306	likely benign	Lynch syndrome 1	2023-12-12	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: 27363726].
PreventionGenetics, part of Exact Sciences	RCV003416032	SCV004115037	uncertain significance	MSH2-related condition	2024-02-05	criteria provided, single submitter	clinical testing	The MSH2 c.1790A>C variant is predicted to result in the amino acid substitution p.Asp597Ala. This variant has been reported in an individual with hypodiploid acute lymphoblastic leukemia (Table S4A, Zhang et al. 2015. PubMed ID: 26580448). In addition, this variant is observed once and interpreted as variant of uncertain significance in a cohort study of 4740 patients with Lynch syndrome associated cancer (Table S5, Li et al 2020. PubMed ID: 31391288). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/183758/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.