ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164083 SCV000214693 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000164083 SCV000911412 likely benign Hereditary cancer-predisposing syndrome 2016-05-16 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000781574 SCV000919729 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2030G>C (p.Ser677Thr) variant located in the DNA mismatch repair protein MutS, connector domain (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a benign outcome for this variant. A functional study, Kantelinen_2012, supports these predictions observing the variant to act comparable to wild type MMR activity. This variant is absent in 245448 control chromosomes (gnomAD). A publication, Kantelinen_2012, observed the variant in a 38 y/o CrC pt, who carried another VUS MSH6 variant, Leu585Pro, which showed an affect on MMR activity suggesting that this variant may be the disease-causing variant, therefore, supporting the variant of interest beinging in the benign spectrum. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance - possibly benign."
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074704 SCV000107911 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000553788 SCV000624717 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-05 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.

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