ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.791A>G (p.Gln264Arg) (rs730881780)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160640 SCV000211242 uncertain significance not provided 2014-10-09 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.791A>G at the cDNA level, p.Gln264Arg (Q264R) 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 Gln264Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Gln264Arg occurs at a position that is well conserved across species and is located in the connector domain (Lutzen 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH2 Gln264Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000798669 SCV000938295 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 264 of the MSH2 protein (p.Gln264Arg). The glutamine residue is moderately 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 conditions. ClinVar contains an entry for this variant (Variation ID: 182600). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV001184011 SCV001349881 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-15 criteria provided, single submitter clinical testing

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