ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1937A>G (p.Lys646Arg) (rs201096652)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229693 SCV000283737 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 646 of the MSH6 protein (p.Lys646Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs201096652, ExAC 0.07%). This variant has been reported in an individual affected with breast cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 237148). An algorithm developed specifically for MSH6 (PMID: 23621914), as well as general algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000482874 SCV000565219 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1937A>G at the cDNA level, p.Lys646Arg (K646R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has been reported in an individual with breast cancer (Lu 2015). MSH6 Lys646Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Lys646Arg is located in the connector domain (Warren 2007, Kansikas 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 Lys646Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491214 SCV000580205 likely benign Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
Color RCV000491214 SCV000685240 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing

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