ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3992G>A (p.Arg1331Gln) (rs184131049)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482748 SCV000568116 uncertain significance not provided 2020-12-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; Has not been previously reported as pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 26991699, 22851212, 27294619)
Ambry Genetics RCV000491185 SCV000580208 likely benign Hereditary cancer-predisposing syndrome 2020-07-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000707566 SCV000836667 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 1331 of the MSH6 protein (p.Arg1331Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 419915). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482748 SCV001134450 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing
Mendelics RCV000986744 SCV001135856 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491185 SCV001352057 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-19 criteria provided, single submitter clinical testing

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