ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2030G>C (p.Ser677Thr) (rs587779224)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164083 SCV000214693 likely benign Hereditary cancer-predisposing syndrome 2019-04-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000223471 SCV000279786 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2030G>C at the cDNA level, p.Ser677Thr (S677T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). This variant has been observed in at least one individual with early-onset colorectal cancer, in co-occurrence with another MSH6 missense variant (Kantelinen 2012). Kantelinen et al. (2012) demonstrated that MSH6 Ser677Thr had greater than 100% relative repair activity in a MMR complementation assay and that MSH6 expression was comparable to wild-type. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MSH6 Ser677Thr as a variant of uncertain significance, based on insufficient evidence (Thompson 2014). MSH6 Ser677Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ser677Thr occurs at a position that is conserved in mammals and is located within the MutS II domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Therefore, based on the currently available evidence, it is unclear whether MSH6 Ser677Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000553788 SCV000624717 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-17 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 677 of the MSH6 protein (p.Ser677Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal cancer (PMID: 22581703). ClinVar contains an entry for this variant (Variation ID: 89240). Experimental studies suggest that this variant does not affect MSH6 protein function (PMID: 22581703). 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.
Color RCV000164083 SCV000911412 likely benign Hereditary cancer-predisposing syndrome 2016-05-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781574 SCV000919729 uncertain significance not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2030G>C (p.Ser677Thr) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. A functional study, Kantelinen_2012, supports these predictions reporting the variant to have comparable to wild-type MMR activity. The variant was absent in 250724 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2030G>C has been reported in a 38 y/o CrC patient who carried another MSH6 variant, Leu585Pro, which showed decreasing on MMR activity suggesting that this variant may be the disease-causing variant, therefore, supporting the variant of interest being in the benign spectrum (Kantelinen_2012). Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (1x) and uncertain significance (3x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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