ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2079dup (p.Cys694fs) (rs267608083)

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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 RCV000167251 SCV000218091 pathogenic Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657407 SCV000779142 pathogenic not provided 2018-10-04 criteria provided, single submitter clinical testing This duplication of one nucleotide in MSH6 is denoted c.2079dupA at the cDNA level and p.Cys694MetfsX4 (C694MfsX4) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CAAAAA[dupA]TGCC. The duplication causes a frameshift which changes a Cysteine to a Methionine at codon 694, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2079dupA has been reported in individuals with personal and/or a family history of colorectal cancer (Shirts 2016, Hansen2017). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000629924 SCV000750880 pathogenic Hereditary nonpolyposis colon cancer 2017-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys694Metfs*4) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333) and an individual with colorectal cancer (PMID: 28195393). ClinVar contains an entry for this variant (Variation ID: 187516). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657407 SCV000889469 pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210176 SCV000266091 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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