ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3119_3120del (p.Asn1039_Phe1040insTer) (rs267608042)

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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 RCV000491377 SCV000580131 pathogenic Hereditary cancer-predisposing syndrome 2018-03-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion),Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000491377 SCV000685354 pathogenic Hereditary cancer-predisposing syndrome 2017-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000486939 SCV000568724 pathogenic not provided 2016-08-18 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted MSH6 c.3119_3120delTT at the cDNA level and p.Phe1040Ter (F1040X) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACT[TT]GATA. The deletion creates a nonsense variant, which changes a Phenylalanine 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.3119_3120delTT has been reported in an individual with a personal history of duodenal cancer and family history of colon cancer whose tumor demonstrated microsatellite instability and lack of MSH6 protein expression (Roncari 2007), as well as in an individual with a personal history of early-onset cecal cancer and family history of colorectal and other Lynch-associated cancers (Cruz-Correa 2015). We consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074804 SCV000108015 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000531248 SCV000624817 pathogenic Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1040*) 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 reported in 2 individuals affected with hereditary non-polyposis colorectal cancer (PMID: 17718861, 25782445). ClinVar contains an entry for this variant (Variation ID: 89339). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.

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