ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1705_1706del (p.Phe569fs) (rs587783056)

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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 RCV000216742 SCV000274941 pathogenic Hereditary cancer-predisposing syndrome 2018-02-26 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)
Color RCV000216742 SCV000905451 pathogenic Hereditary cancer-predisposing syndrome 2018-03-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780461 SCV000917728 pathogenic Lynch syndrome 2018-12-28 criteria provided, single submitter clinical testing Variant summary: The variant, MSH6 c.1705_1706delTT (p.Phe569HisfsX7) 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 (eg. c.1784delT (p.Leu595fsX15), c.2150_2153delTCAG (p.Val717fsX18)). The variant allele was found at a frequency of 3.2e-05 in 30970 control chromosomes. c.1705_1706delTT has been reported in the literature in an individual affected with colon cancer (Foley_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000542464 SCV000624682 pathogenic Hereditary nonpolyposis colon cancer 2018-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe569Hisfs*7) 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 an individual with colon cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 156507). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Pathway Genomics RCV000144627 SCV000189954 pathogenic Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing

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