ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1130A>G (p.Gln377Arg) (rs776174711)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229489 SCV000284092 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 377 of the MSH2 protein (p.Gln377Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs776174711, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 237358). 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.
GeneDx RCV000479748 SCV000570113 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1130A>G at the cDNA level, p.Gln377Arg (Q377R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln377Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln377Arg occurs at a position that is conserved across species and is located in the Lever domain (L?tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gln377Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662583 SCV000785206 uncertain significance Lynch syndrome I 2017-06-02 criteria provided, single submitter clinical testing
Mendelics RCV000708830 SCV000837826 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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