ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2615T>C (p.Ile872Thr) (rs1064793342)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487290 SCV000565867 uncertain significance not provided 2017-08-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2615T>C at the cDNA level, p.Ile872Thr (I872T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile872Thr was not observed 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 Ile872Thr occurs at a position that is not conserved and is located in the Lever 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 Ile872Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000552497 SCV000624779 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 872 of the MSH6 protein (p.Ile872Thr). The isoleucine residue is weakly 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 disease. ClinVar contains an entry for this variant (Variation ID: 418649). 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 tolerated, but these predictions have not been confirmed by published functional studies and their 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.
Ambry Genetics RCV000567884 SCV000662377 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing
Color RCV000567884 SCV000911268 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing

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