Characterisation of a Portuguese origin founder missense variant in MSH6

In certain populations, founder pathogenic variants are a common cause of Lynch syndrome. Here, we report the identification of a novel Portuguese founder variant, NM_000179.3 (MSH6):c.2061 T > G (p.Cys687Trp). Our study examined 14 probands and 19 additional family members who carry this variant. With one exception, haplotype data are consistent with a single origin for all heterozygotes, likely in the Leiria District of Portugal. We investigated the clinicopathological consequences of this variant and found that, as previously reported for MSH6 pathogenic variants, (a) the presence of a pathogenic variant is not reliably associated with loss of MSH6 expression or microsatellite instability and (b) endometrial cancer is the most common associated phenotype. Due to the requirement to apply the BP5 code according to ACMG criteria, the variant is classified as a variant of uncertain significance rather than likely pathogenic. Nevertheless, the balance of evidence we present here suggests that this variant is associated with an increased risk for MSH6-related Lynch syndrome tumors.