ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3740C>G (p.Thr1247Ser) (rs786204182)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168238 SCV000218907 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 1247 of the MSH6 protein (p.Thr1247Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. 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: 188262). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000214013 SCV000276887 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000484522 SCV000571557 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3740C>G at the cDNA level, p.Thr1247Ser (T1247S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr1247Ser was not observed in large population cohorts (Lek 2016). This variant is located within 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 Thr1247Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000214013 SCV000685439 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Counsyl RCV000662602 SCV000785239 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780480 SCV000917764 uncertain significance not specified 2018-05-30 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3740C>G (p.Thr1247Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245976 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3740C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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