ClinVar Miner

Submissions for variant NM_001281492.1(MSH6):c.2145dup (p.Glu716Ter) (rs587779241)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074751 SCV000107961 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Counsyl RCV000410929 SCV000488331 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-03-08 criteria provided, single submitter clinical testing
Invitae RCV000530811 SCV000624767 pathogenic Hereditary nonpolyposis colorectal neoplasms 2017-06-13 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 4 of the MSH6 mRNA (c.2535dupT) This creates a premature translational stop signal (p.Glu846*) and is expected to result in an absent or disrupted protein product. 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 Lynch syndrome (PMID: 20487569). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074751 SCV000695817 likely pathogenic Lynch syndrome 2017-06-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2535dupT (p.Glu846X) 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.2731C>T, p.Arg911X; c.3013C>T, p.Arg1005X; c.3052_3053delCT, p.Leu1018fsX4). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120004 control chromosomes. The variant was reported in a family that fulfilled the Amsterdam II criteria, however two mutation-positive family members did not have cancer, one of which was above the age of onset. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, based on truncating nature of the variant, and the limited clinical data, this variant is classified as likely pathogenic.
Ambry Genetics RCV001015798 SCV001176673 pathogenic Hereditary cancer-predisposing syndrome 2018-02-01 criteria provided, single submitter clinical testing The c.2535dupT pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of T at nucleotide position 2535, causing a translational frameshift with a predicted alternate stop codon (p.E846*). This mutation has been previously reported in a cohort of Australian Lynch syndrome families (Talseth-Palmer BA et al. Hered Cancer Clin Pract. 2010 May;8:5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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