ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1538T>C (p.Ile513Thr) (rs1060502908)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456298 SCV000551139 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 513 of the MSH6 protein (p.Ile513Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 410453). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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 RCV000484466 SCV000572201 uncertain significance not provided 2018-05-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1538T>C at the cDNA level, p.Ile513Thr (I513T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATC>ACC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Ile513Thr was not observed in large population cohorts (Lek 2016). This variant is located in the mismatch binding 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 Ile513Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000567923 SCV000670082 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000567923 SCV000685200 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing

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