ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3799_3800del (p.Met1267fs) (rs267608114)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074931 SCV000108144 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000491355 SCV000580237 pathogenic Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing The c.3799_3800delAT pathogenic mutation, located in coding exon 8 of the MSH6 gene, results from a deletion of two nucleotides at nucleotide positions 3799 to 3800, causing a translational frameshift with a predicted alternate stop codon (p.M1267Gfs*7). <span style="background-color:initial">This pathogenic mutation has been <span style="background-color:initial">reported in one Danish family diagnosed with Lynch syndrome/HNPCC (Nilbert M et al. Fam Cancer. 2009;8(1):75-83). 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.
GeneDx RCV000202066 SCV000617714 pathogenic not provided 2017-06-02 criteria provided, single submitter clinical testing This deletion of two nucleotides in MSH6 is denoted c.3799_3800delAT at the cDNA level and p.Met1267GlyfsX7 (M1267GfsX7) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAT[delAT]GGTA. The deletion causes a frameshift which changes a Methionine to a Glycine at codon 1267, and creates a premature stop codon at position 7 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.3799_3800delAT has been reported in individuals with Lynch syndrome (Nilbert 2009, Klarskov 2011). We consider this variant to be pathogenic.
Invitae RCV000703066 SCV000831947 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-05-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met1267Glyfs*7) 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 an individual with clinical features of Lynch syndrome (PMID: 18566915, 21836479). ClinVar contains an entry for this variant (Variation ID: 89463). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000074931 SCV000919751 pathogenic Lynch syndrome 2018-07-03 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3799_3800delAT (p.Met1267GlyfsX7) 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 (eg. c.3840_3846delGGAGACT, p.Glu1281fsX44; c.3938_3941dupTTCA, p.Gln1314fsX6; c.3939_3940dupTC, p.Gln1314fsX14). The variant was absent in 276958 control chromosomes (gnomAD). The variant, c.3799_3800delAT, has been reported in the literature in individuals affected with Lynch Syndrome (Nilbert_2009) and also as a somatic mutation in prostate cancer (Pritchard_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202066 SCV001134443 pathogenic not provided 2019-08-20 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Mayo Clinic Laboratories, Mayo Clinic RCV000202066 SCV000257279 likely pathogenic not provided no assertion criteria provided research

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