ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.38A>C (p.Lys13Thr) (rs41294988)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160705 SCV000211335 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.38A>C at the cDNA level, p.Lys13Thr (K13T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant was observed in one individual with colorectal cancer and was not observed in 1,104 controls; however, the colorectal tumor was microsatellite stable and MSH6 was present by immunohistochemistry testing (Barnetson 2008). MSH6 Lys13Thr was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Lys13Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000627725 SCV000551144 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 13 of the MSH6 protein (p.Lys13Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with colorectal cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 36596). 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 disruptive. However, and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. 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.
Ambry Genetics RCV000569787 SCV000662392 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-06 criteria provided, single submitter clinical testing
Color RCV000569787 SCV000685459 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Counsyl RCV000662751 SCV000785534 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-09-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030274 SCV000052941 uncertain significance Lynch syndrome 2015-10-02 no assertion criteria provided clinical testing

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