ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2780T>C (p.Ile927Thr) (rs587779926)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587183 SCV000149304 uncertain significance not provided 2019-01-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2780T>C at the cDNA level, p.Ile927Thr (I927T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Immunohistochemistry (IHC) performed on a colorectal tumor from an individual heterozygous for MSH6 Ile927Thr demonstrated loss of MLH1 and PMS2 in the presence of hypermethylation of the MLH1 promoter (Terui 2013). This variant was also identified in an individual with a low grade glioma (Lu 2015). MSH6 Ile927Thr was observed at an allele frequency of 0.01% (2/18,860) in individuals of East Asian ancestry in large population cohorts (Lek 2016). MSH6 Ile927Thr is located within the lever 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 Ile927Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115395 SCV000215177 likely benign Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV000206053 SCV000260782 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 927 of the MSH6 protein (p.Ile927Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587779926, ExAC 0.002%). This variant has been reported in individuals affected with colorectal cancer and glioma (PMID: 24100870, 26689913). ClinVar contains an entry for this variant (Variation ID: 127574). 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, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212671 SCV000601542 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing
Color RCV000115395 SCV000690290 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587183 SCV000695830 uncertain significance not provided 2016-12-09 criteria provided, single submitter clinical testing Variant summary: The c.2780C>T (p.Ile927Thr) in MSH6 gene is a missense change that involves a conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant of interest was identified in at least one CRC pt with alternative cause of the disease (IHC showed lack of MLH1/PMS2 staining due to MLH1 promoter methylation, but normal staining for MSH2/6). The variant is present in large control population dataset of ExAC at a frequency 0.0000083 (1/120702 tested). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic variant in this gene (0.0001). The variant was identified in an internal sample undergoing genetic testing, which also carried c.1100delC in CHEk2 gene. Lastly, several reputable databases/clinical laboratories cite the variant as VUS. It is likely that c.2780C>T represents rare functional missense change, at this time there is no sufficient evidence to classify this variant with confidence. Taken together, the variant was classified as VUS.

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