ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1189C>G (p.Gln397Glu) (rs63750611)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
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 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 397 of the MSH2 protein (p.Gln397Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs63750611, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182594). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000491315 SCV000580523 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-25 criteria provided, single submitter clinical testing The p.Q397E variant (also known as c.1189C>G), located in coding exon 7 of the MSH2 gene, results from a C to G substitution at nucleotide position 1189. The glutamine at codon 397 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc 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 I 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 ( 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.