SinoXivCharacterisation of a Portuguese origin founder missense variant in MSH6
Abstract
In certain populations, founder pathogenic variants are a common cause of Lynch syndrome. Here, we report the identification of a novel founder variant, NM_000179.3 (MSH6):c.2061T > G (p.Cys687Trp). Our study examined 14 probands and 18 additional family members who carry this variant. With one exception, haplotype data are consistent with a single origin for all heterozygotes. We investigated the clinicopathological consequences of this variant and found that, as previously reported for other MSH6 pathogenic variants a) presence of the founder pathogenic variant is not reliably associated with loss of MSH6 expression or microsatellite instability and b) endometrial cancer is the most common associated phenotype. Based on our findings, we recommend reclassifying MSH6 c.2061T > G from missense variant of unknown significance to likely pathogenic according to CanVIG-UK guidelines.
Keywords
Citation Information
@article{williamfoulkes2026,
title={Characterisation of a Portuguese origin founder missense variant in MSH6},
author={William Foulkes and Kenzie Melvill and Leora Witkowski and Céline Domecq and Nancy Hamel and Justin Mayers and Sofia Maia and Manuel Teixeira and Inês Francisco and Cristina Albuquerque and Olivia Tan and Kevin McDonnell and Alexandra Capasso and George Chong and Victoria Marcus and Carla Pinto},
journal={European Journal of Human Genetics},
year={2026},
doi={https://doi.org/10.21203/rs.3.rs-9172566/v1}
}
