ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1635_1636AG[1] (p.Glu546fs) (rs267608076)

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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 RCV000575511 SCV000662350 pathogenic Hereditary cancer-predisposing syndrome 2016-05-16 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 RCV000217244 SCV000279610 pathogenic not provided 2016-01-27 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in MSH6 is denoted c.1637_1638delAG at the cDNA level and p.Glu546GlyfsX16 (E546GfsX16) at the protein level. The normal sequence, with the bases that are deleted in braces, is AAAG[AG]GAAG. The deletion causes a frameshift, which changes a Glutamic Acid to a Glycine at codon 546, and creates a premature stop codon at position 16 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.1637_1638delAG, also published as c. 1635_1636delAG, has been identified in at least three individuals with Lynch syndrome related cancers (Hampel 2006, Baglietto 2010. Chubb 2015). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074676 SCV000695790 pathogenic Lynch syndrome 2016-04-26 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense medicated decay or produce a truncated protein. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in affected individuals via multiple publications. In addition, a reputable database classifies the variant as "causal." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074676 SCV000107879 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000529714 SCV000624672 pathogenic Hereditary nonpolyposis colon cancer 2018-11-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu546Glyfs*16) 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 the literature in individuals with Lynch syndrome-associated cancers (PMID: 20028993, 26787237, 16885385, 25559809). This variant is also known as c.1635_1636delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 89213). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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