ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233857 SCV000283810 pathogenic Hereditary nonpolyposis colon cancer 2020-01-08 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.
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.
Ambry Genetics RCV000491652 SCV000580315 pathogenic Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Integrated Genetics/Laboratory Corporation of America RCV001194361 SCV001363847 likely pathogenic Hereditary nonpolyposis colon cancer 2019-06-05 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3528_3532delACTTG (p.Leu1177CysfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (c.3573dupT, p.Val1192CysfsX2; c.3609_3612delTGCA, p.His1203fsX12; c.3699_3702delAGAA, p.Lys1233fsX6). The variant was absent in 251266 control chromosomes (gnomAD). The variant, c.3528_3532delACTTG, has been reported in the literature in at least one individual in a study of MSH6 mutation carriers (Baglietto_2010). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202131 SCV000257262 likely pathogenic not provided no assertion criteria provided research

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