ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.905G>A (p.Arg302Lys) (rs587781510)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195580 SCV000254337 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 302 of the MSH6 protein (p.Arg302Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is present in population databases (rs587781510, ExAC 0.002%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658). However, in that individual a pathogenic variant was also identified in MSH6, which suggests that this c.905G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 216324). 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 lysine 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.
Ambry Genetics RCV000219538 SCV000273276 likely benign Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing In silico models in agreement (benign)
GeneDx RCV000521245 SCV000616788 uncertain significance not provided 2019-05-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30212499)
Color Health, Inc RCV000219538 SCV001353864 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-16 criteria provided, single submitter clinical testing This missense variant replaces arginine with lysine at codon 302 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GenomeConnect, ClinGen RCV000845040 SCV000986877 not provided Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 11/07/2016 by GTR ID Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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