ClinVar Miner

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

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Total submissions: 7
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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 colorectal neoplasms 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 RCV000212671 SCV000695830 uncertain significance not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2780T>C (p.Ile927Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250950 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2780T>C has been reported in the literature in at least one colorectal cancer patient (immunohistochemistry on the patient's tumor sample displayed lack of MLH1/PMS2 staining; MLH1 promoter hypermethylation was noted) (Terui_2013). In addition, the variant has been reported in individuals affected with breast cancer and low grade glioma (e.g. Lu_2015, Tung_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. A co-occurrence with a pathogenic variant has been reported (CHEK2 c.1100delC, p.Thr367MetfsX15; Internal testing). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance, while one ClinVar submitter (evaluation after 2014) cites the variant as likely benign reporting it seen in trans with a mutation or in homozygous state in individual without severe disease for the gene (SCV000215177.4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253566 SCV001429352 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-09-30 criteria provided, single submitter clinical testing

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