ClinVar

Description

Variant summary: MSH6 c.3848_3850dupTTA (p.Ile1283dup) results in an in-frame duplication with the insertion of one amino acid into the C-terminal domain of the MSH6 protein (IPR000432). The variant allele was found at a frequency of 2.5e-05 in 282272 control chromosomes, predominantly found in the European subpopulation with an allele frequency of 5.4e-05 in the gnomAD database. However, the variant was found at an even higher frequency in the Swedish (5/26108 alleles; allele frequency of ~0.0002); and this frequency is higher than the maximum expected for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting a benign role for the variant. The variant, c.3848_3850dupTTA, has been reported in the literature in Scandinavian individuals affected with colon cancer and suspected Lynch syndrome (Hansen_2014, Lagerstedt-Robinson_2016, Haraldsdottir_2017), but was also reported to be found with similar allele frequencies among healthy Icelandic controls (Haraldsdottir_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.