ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3026A>T (p.Lys1009Ile) (rs587781593)

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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 RCV000129648 SCV000184445 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000459156 SCV000551231 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 1009 of the MSH6 protein (p.Lys1009Ile). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs587781593, ExAC 0.006%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141232). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000480608 SCV000567036 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3026A>T at the cDNA level, p.Lys1009Ile (K1009I) at the protein level, and results in the change of a Lysine to an Isoleucine (AAA>ATA). MSH6 Lys1009Ile has been observed in at least one individual with breast cancer (Caminsky 2016). MSH6 Lys1009Ile was observed at an allele frequency of 0.007% (8/114354) in individuals of European ancestry in large population cohorts (Lek 2016). MSH6 Lys1009Ile is located within the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Lys1009Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129648 SCV000690310 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing

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