ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3814_3827dup (p.Asp1277fs) (rs1558393070)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000700703 SCV000829470 pathogenic Hereditary nonpolyposis colon cancer 2018-05-17 criteria provided, single submitter clinical testing This sequence change duplicates 14 nucleotides from exon 9 of the MSH6 mRNA (c.3814_3827dup), causing a frameshift at codon 1277. This creates a premature translational stop signal in the penultimate exon of the MSH6 mRNA (p.Asp1277Lysfs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. A different truncation (p.Leu1330Valfs*12) that lies downstream of this variant has been determined to be pathogenic (PMID: 19851887, 24440087, 14520694, 21155762). This suggests that deletion of this region of the MSH6 protein is causative of disease. While no functional studies have been performed to test the effects of this particular variant on MSH6 protein function or stability, it is expected to delete the C-terminal portion of the conserved MutS domain (PMID: 17531815, 24100870). This domain is necessary for the heterodimerization of MSH6 and MSH2 (PMID: 15952900, 16464007). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000780486 SCV000917776 likely pathogenic Lynch syndrome 2017-12-05 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3814_3827dupGAAAATGAATGTGA (p.Asp1277LysfsX55) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 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 (e.g. c.3840_3846delGGAGACT (p.Glu1281fsX44), c.3938_3941dupTCCA (p.Gln1314fsX6), and c.3939_3957dupTCAAAAGGGACATAGAAAA (p.Ala1320fsX5)). This variant is absent in 245872 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985847 SCV001134444 pathogenic not provided 2019-06-20 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.

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