ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3604A>G (p.Met1202Val) (rs369778514)

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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 RCV000129582 SCV000184364 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000411815 SCV000488741 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000479516 SCV000565928 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3604A>G at the cDNA level, p.Met1202Val (M1202V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met1202Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Met1202Val is located within the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Met1202Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129582 SCV000685419 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780465 SCV000917737 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The c.3604A>G (p.Met1202Val) variant in the MSH6 gene is a missense variant that involves a mildly conserved nucleotide and 5/5 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The c.3604A>G is present in the control population datasets of ExAC and gnomAD at a low frequency (1/121324 and 2/246248 chrs tested, respectively). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0001, suggesting that it is not a common polymorphism. To our knowledge, the variant has not been reported in affected individuals via peer-reviewed reports, but is cited as VUS by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Invitae RCV000810760 SCV000950993 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1202 of the MSH6 protein (p.Met1202Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs369778514, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141188). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its 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.

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