ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3939_3940dup (p.Gln1314fs) (rs730881830)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497290 SCV000211389 pathogenic not provided 2020-12-14 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals undergoing multi-gene panel testing (Susswein 2016, Espenschied 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26681312, 28152038, 28514183, 31447099)
Ambry Genetics RCV000160746 SCV000273240 pathogenic Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing The c.3939_3940dupTC pathogenic mutation, located in coding exon 9 of the MSH6 gene, results from a duplication of TC at nucleotide position 3939, causing a translational frameshift with a predicted alternate stop codon (p.Q1314Lfs*14). This mutation has been identified in an individual who was diagnosed with bladder and colorectal cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260256 SCV000695900 pathogenic Hereditary nonpolyposis colon cancer 2020-09-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3939_3940dupTC (p.Gln1314LeufsX14) 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. The variant was absent in 249986 control chromosomes. c.3939_3940dupTC has been reported in the literature in an individual affected with colorectal and bladder cancer (Susswein_2015) and in an individual screened for MMR mutations (phenotype not specified, Espenschied_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000590196 SCV000711783 likely pathogenic Lynch syndrome 2017-08-23 criteria provided, single submitter clinical testing The p.Gln1314fs variant in MSH6 has been reported in 1 individual with colorecta l and bladder cancer and 1 individual with unspecified cancer (Susswein 2015, Es penschied 2017). It has also been reported in ClinVar (Variation ID 182683) and was absent from large population studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a f rameshift, which alters the protein?s amino acid sequence beginning at position 1314 and leads to a premature termination codon 14 amino acids downstream. This termination codon occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD), resulting in a trun cated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In summary, although additional studies ar e required to fully establish its clinical significance, the p.Gln1314fs variant is likely pathogenic.
Invitae RCV000698894 SCV000827583 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-09-11 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MSH6 gene (p.Gln1314Leufs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with colorectal and bladder cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182683). A different truncation downstream of this variant (p.Leu1330Valfs*12), is a known Lynch syndrome founder mutation in the Ashkenazi Jewish population. This variant has been shown to abolish MSH6 expression and cause tumor microsatellite instability (PMID: 19851887). It has also been reported in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087), and segregated with disease in a family affected with colorectal cancer (PMID: 14520694). This suggests that deletion of this region of the MSH6 protein is causative of disease For these reasons, this variant has been classified as Pathogenic.

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