Submissions for variant NM_000251.3(MSH2):c.1189C>G (p.Gln397Glu)

gnomAD frequency: 0.00004  dbSNP: rs63750611

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160634	SCV000211235	uncertain significance	not provided	2018-06-12	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.1189C>G at the cDNA level, p.Gln397Glu (Q397E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAA>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign germline variant. MSH2 Gln397Glu was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located within the lever domain as well as the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Gln397Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000233011	SCV000284096	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491315	SCV000580523	benign	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Color Diagnostics, LLC DBA Color Health	RCV000491315	SCV000689961	likely benign	Hereditary cancer-predisposing syndrome	2020-01-17	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257466	SCV001434269	uncertain significance	Lynch syndrome 1	2019-12-21	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.000045 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269197	SCV001448495	uncertain significance	not specified	2020-11-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1189C>G (p.Gln397Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core (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 4.4e-05 in 251454 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (4.4e-05 vs 0.00057), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1189C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have 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). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160634	SCV004220939	uncertain significance	not provided	2023-01-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (10/34586 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported to have a neutral impact on gene function (PMID: 33357406 (2021)), however further research is required. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.