ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3163G>A (p.Ala1055Thr) (rs587779254)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218375 SCV000279902 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3163G>A at the cDNA level, p.Ala1055Thr (A1055T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was reported in an individual with colorectal cancer and hundreds of colorectal polyps, who also carried an APC pathogenic variant (Ricker 2017). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain clinical significance (Thompson 2014). MSH6 Ala1055Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the lever 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 Ala1055Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409200 SCV000487926 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-08 criteria provided, single submitter clinical testing
Invitae RCV000627700 SCV000551239 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1055 of the MSH6 protein (p.Ala1055Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587779254, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 89342). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"), while an algorithm developed specifically for the MSH6 gene predicts that this missense change is likely to affect protein function (PMID: 23621914). The threonine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV000565213 SCV000662417 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000764427 SCV000895484 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000565213 SCV000906524 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing

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