ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.578del (p.Leu193fs) (rs587782281)

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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 RCV000162426 SCV000212773 pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000231303 SCV000283849 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu193Trpfs*18) 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 individuals undergoing hereditary cancer panel testing (PMID: 24763289, 28514183). ClinVar contains an entry for this variant (Variation ID: 183724). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000480253 SCV000568719 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH6 is denoted c.578delT at the cDNA level and p.Leu193TrpfsX18 (L193WfsX18) at the protein level. The normal sequence, with the base that is deleted in braces, is GAAT[T]GGCA. The deletion causes a frameshift which changes a Leucine to a Tryptophan at codon 193, and creates a premature stop codon at position 18 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.578delT has been observed in at least one individual who had multi-gene panel testing due to a personal and/or family history suggestive of a hereditary cancer syndrome (LaDuca 2014). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480253 SCV001134452 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Integrated Genetics/Laboratory Corporation of America RCV001193128 SCV001361765 pathogenic Hereditary nonpolyposis colon cancer 2019-05-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.578delT (p.Leu193TrpfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251422 control chromosomes. c.578delT has been reported in the literature in individuals being tested with a multi-gene cancer panel (Espenschied_2017, LaDuca_2014, Roberts_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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