ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3939_3940dupTC (p.Gln1314Leufs) (rs730881830)

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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 RCV000160746 SCV000273240 pathogenic Hereditary cancer-predisposing syndrome 2017-09-01 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 RCV000497290 SCV000211389 pathogenic not provided 2017-08-29 criteria provided, single submitter clinical testing The MSH6 c.3939_3940dupTC duplication causes a frameshift, which changes a Glutamine to a Leucine at codon 1314, and creates a premature stop codon at position 14 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 47 amino acids are replaced by 13 incorrect ones, disrupting an MSH2 binding site and a portion of the ATPase domain (Kariola 2002, Warren 2007, Kansikas 2011). This variant is predicted to cause loss of normal protein function through protein truncation. MSH6 c.3939_3940dupTC has been reported in an individual with colorectal and bladder cancer (Susswein 2016) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000590196 SCV000695900 pathogenic Lynch syndrome 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3939_3940dupTC (p.Gln1314Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Frameshift variants downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3959_3962delCAAG [p.Ala1320fs). The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP), but it has been reported in an affected individual via a publication (Susswein et al 2015). In addition, multiple reputable clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000698894 SCV000827583 pathogenic Hereditary nonpolyposis colon cancer 2018-02-13 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000590196 SCV000711783 likely pathogenic Lynch syndrome 2017-09-26 criteria provided, single submitter clinical testing The p.Gln1314fs variant in MSH6 has been reported in 1 individual with colorectal and bladder cancer and 1 individual with unspecified cancer (Susswein 2015, Espenschied 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 frameshift, 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 truncated protein. Truncating variants downstream of this variant have been reported in individuals with Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln1314fs variant is likely pathogenic.

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