ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3528_3532del (p.Leu1177fs) (rs863225408)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491652 SCV000580315 pathogenic Hereditary cancer-predisposing syndrome 2018-04-16 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)
GeneDx RCV000202131 SCV000568728 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing This deletion of 5 nucleotides in MSH6 is denoted c.3528_3532delACTTG at the cDNA level and p.Leu1177CysfsX9 (L1177CfsX9) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTAG[ACTTG]GTGC. The deletion causes a frameshift which changes a Leucine to a Cysteine at codon 1177, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.3528_3532delACTTG has been observed in at least one family with Lynch syndrome (Baglietto 2010). We consider this variant to be pathogenic.
Invitae RCV000233857 SCV000283810 pathogenic Hereditary nonpolyposis colon cancer 2017-05-16 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 6 of the MSH6 mRNA (c.3528_3532delACTTG), causing a frameshift at codon 1177. This creates a premature translational stop signal (p.Leu1177Cysfs*9) and is expected to result in an absent or disrupted protein product. Truncating variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). This particular variant has been reported in an individual from a study of MSH6 mutation carriers (PMID: 20028993). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202131 SCV000257262 likely pathogenic not provided no assertion criteria provided research

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