Characterisation of a Portuguese origin founder missense variant in MSH6.

MSH6

Founder MSH6 missense variant c.2061T>G (p.Cys687Trp), likely of single origin in the Leiria District (Portugal), classified as of uncertain significance under ACMG criteria

In certain populations, founder pathogenic variants are a common cause of Lynch syndrome. The authors report a novel Portuguese founder variant in MSH6, NM_000179.3:c.2061T>G (p.Cys687Trp), carried by 14 probands and 19 additional family members; with one exception, haplotype data are consistent with a single origin, likely in the Leiria District. As previously reported for MSH6 pathogenic variants, the variant is not reliably associated with loss of MSH6 expression or microsatellite instability, and endometrial cancer is the most common associated phenotype. Because the BP5 ACMG code must be applied, the variant is classified as of uncertain significance rather than likely pathogenic. Nevertheless, the balance of evidence suggests that it is associated with an increased risk of MSH6-related Lynch syndrome tumors.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This work illustrates a concrete limitation of the ACMG framework: a single criterion (BP5) keeps as of uncertain significance a variant that the authors' overall evidence associates with increased risk. For clinicians, the frequent absence of MSH6 expression loss and microsatellite instability is a reminder that negative tumor screening does not rule out MSH6-related Lynch syndrome. With 33 carriers, the sample is too small to quantify risk, leaving the management of relatives to the judgement of clinical teams.

Analysis by Dr Thibaut Benquey