ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2348_2349del (p.Leu782_Cys783insTer) (rs267608065)

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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 RCV000491787 SCV000580301 pathogenic Hereditary cancer-predisposing syndrome 2018-02-20 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)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074739 SCV000592607 pathogenic Lynch syndrome 2015-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000657810 SCV000779565 pathogenic not provided 2017-01-23 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted MSH6 c.2348_2349delGT at the cDNA level and p.Cys783Ter (C783X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CTCT[delGT]AACC. The deletion creates a nonsense variant, which changes a Cysteine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.2348_2349delGT has been reported in two individuals with colorectal cancer whose tumors showed loss of MSH6 protein on immunohistochemistry (Steinke 2008, Talseth-Palmer 2010). This variant is considered pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074739 SCV000107948 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000556290 SCV000624749 pathogenic Hereditary nonpolyposis colon cancer 2018-06-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys783*) 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 observed in individuals affected with colon cancer (PMID: 18301448, 20487569). ClinVar contains an entry for this variant (Variation ID: 89274). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.

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