ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.719G>A (p.Arg240Gln) (rs542848931)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216536 SCV000274698 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000476259 SCV000551299 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 240 of the MSH6 protein (p.Arg240Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs542848931, ExAC 0.01%). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 29575718, 28932927). ClinVar contains an entry for this variant (Variation ID: 230984). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000481509 SCV000570697 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.719G>A at the cDNA level, p.Arg240Gln (R240Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Arg240Gln was not observed at a significant frequency in large population cohorts (Lek 2016). MSH6 Arg240Gln is located in the nuclear localization signal region (Gassman 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 MSH6 Arg240Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659888 SCV000781783 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000216536 SCV000908356 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781606 SCV000919778 uncertain significance not specified 2018-12-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.719G>A (p.Arg240Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.8e-05 in 276782 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.719G>A has been reported in the literature in individuals affected with Lynch Syndrome and in one case the variant co-occurred with a pathogenic variant, suggesting the benign role of the variant of interest (Soares_2017, Schneider_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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