ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219538 SCV000273276 likely benign Hereditary cancer-predisposing syndrome 2015-01-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
GeneDx RCV000521245 SCV000616788 uncertain significance not provided 2018-08-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.905G>A at the cDNA level, p.Arg302Lys (R302K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Arg302Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Arg302Lys is located in the nuclear localization signals (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 Arg302Lys is a pathogenic or benign variant. We consider it to be 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.
Invitae RCV000195580 SCV000254337 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-22 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.

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