ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3880_3892del (p.Cys1294fs)

dbSNP: rs1553333497
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000528164 SCV000624938 pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-09-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Cys1294Metfs*29). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 67 amino acids of the 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. Two similar MSH6 variants, c.3959_3962delCAAG, creating a frameshift at codon 1320 (p.Ala1320Glufs*6), and c.3984_3987dupGTCA, creating a frameshift at codon 1330 (p.Leu1330Valfs*12), have been reported as Ashkenazi Jewish founder mutations known to cause Lynch syndrome (PMID: 21155762). 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.
Myriad Genetics, Inc. RCV003449516 SCV004185854 pathogenic Lynch syndrome 5 2023-08-28 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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