ClinVar Miner

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

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Total submissions: 4
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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 2019-12-21 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 2018-09-30 criteria provided, single submitter clinical testing Insufficient evidence;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Color RCV000491315 SCV000689961 likely benign Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing

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