ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2092C>G (p.Gln698Glu) (rs63750832)

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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 RCV000130187 SCV000185024 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing The p.Q698E variant (also known as c.2092C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2092. The glutamine at codon 698 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been classified as a variant of uncertain significance using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at []). This alteration has been reported in a familial colorectal cancer kindred (Wang Q et al. Hum. Genet. 1999;105:79-85). In addition, this alteration was reported as a VUS in one individual from a Danish hereditary colorectal cancer registry and was reported in an individual with colorectal cancer at age 65 from a Cypriot cohort of 77 patients fulfilling revised Bethesda guidelines (Nilbert M et al. Fam. Cancer. 2009 Jun;8:75-83; Loizidou MA et al. PLoS ONE. 2014 Aug;9:e105501). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000524131 SCV000254291 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 698 of the MSH6 protein (p.Gln698Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs63750832, ExAC 0.009%). This variant has been reported in individuals with colorectal cancer and/or suspected Lynch syndrome (PMID: 10480359, 25133505, 18566915). ClinVar contains an entry for this variant (Variation ID: 89251). Algorithms developed specifically for the MSH6 gene (PMID: 22290698, 23621914), suggest that this missense change is likely to be tolerated. However, 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.
GeneDx RCV000480300 SCV000567405 uncertain significance not provided 2019-01-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2092C>G at the cDNA level, p.Gln698Glu (Q698E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has been observed in at least two individuals with a personal and/or family history of colorectal cancer (Wang 1999, Loizidou 2014). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance based on insufficient evidence (Thompson 2014). MSH6 Gln698Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MSH6 Gln698Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000130187 SCV000685254 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-21 criteria provided, single submitter clinical testing
Counsyl RCV000662368 SCV000784759 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-05-02 criteria provided, single submitter clinical testing

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