ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3452C>G (p.Ala1151Gly) (rs587782625)

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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 RCV000132010 SCV000187069 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000234247 SCV000283807 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 1151 of the MSH6 protein (p.Ala1151Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs587782625, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 142663). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000412120 SCV000488229 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000484116 SCV000567286 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3452C>G at the cDNA level, p.Ala1151Gly (A1151G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala1151Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Ala1151Gly is located in the ATPase domain and in the ATP-binding motif (Kariola 2002, 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 Ala1151Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000708888 SCV000837915 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000132010 SCV000908420 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing

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