Submissions for variant NM_000251.3(MSH2):c.97A>G (p.Thr33Ala)

dbSNP: rs63751107

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000684814	SCV000548275	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000480593	SCV000568619	uncertain significance	not provided	2019-09-18	criteria provided, single submitter	clinical testing	Observed in individuals with suspected Lynch syndrome (Auclair 2006); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 18383312, 16395668, 26951660, 26333163)
Ambry Genetics	RCV000565059	SCV000669761	likely benign	Hereditary cancer-predisposing syndrome	2023-09-11	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	RCV000565059	SCV000685146	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 33 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 detected in a suspected Lynch syndrome family with two MLH1 covariants (PMID: 16395668). This variant has been identified in 3/222782 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.
Mendelics	RCV000076773	SCV000837813	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818242	SCV002066925	uncertain significance	not specified	2017-12-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000076773	SCV004828836	uncertain significance	Lynch syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 33 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 detected in a suspected Lynch syndrome family with two MLH1 covariants (PMID: 16395668). This variant has been identified in 3/222782 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.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004776271	SCV005382091	uncertain significance	Malignant glioma		criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480593	SCV005623699	uncertain significance	not provided	2023-11-28	criteria provided, single submitter	clinical testing	The MSH2 c.97A>G (p.Thr33Ala) variant has been reported in the published literature in a family with hereditary nonpolyposis colon cancer syndrome (HNPCC) (PMID: 16395668 (2006)) as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Functional studies reported this variant had no impact on splicing (PMID: 16395668 (2006)) and was not damaging in a mismatch repair dysfunction assay (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.00003 (3/100194 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.