ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.716A>G (p.Gln239Arg) (rs199676483)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491808 SCV000580504 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491808 SCV000685122 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000411135 SCV000488394 uncertain significance Lynch syndrome I 2016-03-17 criteria provided, single submitter clinical testing
GeneDx RCV000656873 SCV000211225 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.716A>G at the cDNA level, p.Gln239Arg (Q239R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln239Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln239Arg is located in the connector domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Gln239Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000491808 SCV000822056 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000160626 SCV000595838 uncertain significance not specified 2017-06-02 criteria provided, single submitter clinical testing
Invitae RCV000198252 SCV000254427 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-26 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 239 of the MSH2 protein (p.Gln239Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182589). 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 disruptive, 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.
Mendelics RCV000708828 SCV000837821 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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