ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3467T>C (p.Met1156Thr) (rs876659549)

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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 RCV000217088 SCV000276138 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000475398 SCV000551196 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1156 of the MSH6 protein (p.Met1156Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with Lynch syndrome related cancers (Invitae). However, in that individual, a pathogenic allele was also identified in MSH2, which suggests that this c.3467T>C variant was not the primary cause of disease. This variant been reported in an individual with family or personal history of Lynch syndrome or colorectal cancer (PMID:28502729). ClinVar contains an entry for this variant (Variation ID: 232091). 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 C45"). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482975 SCV000568007 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3467T>C at the cDNA level, p.Met1156Thr (M1156T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was observed in a patient that underwent testing for hereditary colon cancer (Rey 2017). MSH6 Met1156Thr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met1156Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Met1156Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217088 SCV000690358 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000662884 SCV000785793 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-11-28 criteria provided, single submitter clinical testing

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