ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3800T>C (p.Met1267Thr) (rs148445930)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132022 SCV000187081 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000230512 SCV000283823 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1267 of the MSH6 protein (p.Met1267Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs148445930, ExAC 0.01%). This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142672). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508216 SCV000601586 uncertain significance not specified 2016-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000589302 SCV000616792 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3800T>C at the cDNA level, p.Met1267Thr (M1267T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has been observed in two individuals with colorectal cancer (Yurgelun 2017). MSH6 Met1267Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase 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 Met1267Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132022 SCV000685445 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589302 SCV000695888 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3800T>C (p.Met1267Thr) variant located in the P-loop containing nucleoside triphosphate hydrolase domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121204, which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Multiple publications that utilized in silico analyses predict the variant to have an impact on MSH6 protein function, although these publications do not functionally assess these predictions. Multiple clinical diagnostic laboratories classified this variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance."
Counsyl RCV000662794 SCV000785607 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-10-02 criteria provided, single submitter clinical testing

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