ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3938_3941dup (p.Gln1314fs) (rs267608126)

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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 RCV000491665 SCV000580378 pathogenic Hereditary cancer-predisposing syndrome 2016-09-09 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)
Integrated Genetics/Laboratory Corporation of America RCV000074953 SCV000695898 pathogenic Lynch syndrome 2016-04-27 criteria provided, single submitter clinical testing Variant summary: The variant of interest results in a frameshift mutation causes a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated 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 an individual diagnosed with endometrial cancer via a publication. A reputable database cites the variant with a classification of "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074953 SCV000108168 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524196 SCV000551181 pathogenic Hereditary nonpolyposis colon cancer 2018-02-25 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 9 of the MSH6 mRNA (c.3938_3941dupTTCA), causing a frameshift at codon 1314. This creates a premature translational stop signal in the penultimate exon of the MSH6 mRNA (p.Gln1314Hisfs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated MSH6 protein. Loss-of-function variants in MSH6 are known to be pathogenic. This particular variant has been reported in the literature in an individual affected with endometrial cancer (PMID: 18269114). ClinVar contains an entry for this variant (Variation ID: 89485). 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). This suggests that deletion of this C-terminal region of the MSH6 protein is causative of disease. While no functional studies have been performed to test the effect 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759145 SCV000888281 pathogenic not provided 2018-08-20 criteria provided, single submitter clinical testing

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