ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1184C>T (p.Thr395Ile) (rs767658494)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210204 SCV000266200 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000481629 SCV000565213 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1184C>T at the cDNA level, p.Thr395Ile (T395I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been observed in at least one individual with skin cancer (Shirts 2016). MSH6 Thr395Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr395Ile occurs at a position where amino acids with properties similar to Threonine are tolerated across species, and is located in the mismatch binding domain and nuclear localization signal domain (Warren 2007, Gassman 2011, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr395Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491003 SCV000580242 uncertain significance Hereditary cancer-predisposing syndrome 2014-07-28 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000559226 SCV000624623 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 395 of the MSH6 protein (p.Thr395Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs767658494, ExAC 0.01%). This variant has been reported in the literature in an individual affected with skin cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224579). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and an affected individual, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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