ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1325T>C (p.Ile442Thr) (rs587779210)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000627712 SCV000259234 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 442 of the MSH6 protein (p.Ile442Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587779210, ExAC 0.03%). This variant has been observed in an individual affected with prostate cancer (PMID: 27701467). ClinVar contains an entry for this variant (Variation ID: 89187). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000213558 SCV000279377 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1325T>C at the cDNA level, p.Ile442Thr (I442T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile442Thr was observed at an allele frequency of 0.03% (2/6614) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ile442Thr occurs at a position that is not conserved and is located within the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Ile442Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568557 SCV000662386 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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