TY - JOUR T1 - Characterisation of heterozygous <em>PMS2</em> variants in French patients with Lynch syndrome JF - Journal of Medical Genetics JO - J Med Genet SP - 487 LP - 499 DO - 10.1136/jmedgenet-2019-106256 VL - 57 IS - 7 AU - Qing Wang AU - Julie Leclerc AU - Gaëlle Bougeard AU - Sylviane Olschwang AU - Stéphanie Vasseur AU - Kévin Cassinari AU - Denis Boidin AU - Cédrick Lefol AU - Pierre Naïbo AU - Thierry Frébourg AU - Marie Pierre Buisine AU - Stéphanie Baert-Desurmont A2 - , Y1 - 2020/07/01 UR - http://jmg.bmj.com/content/57/7/487.abstract N2 - Background Heterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.Methods We report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.Results Genomic rearrangements account for 18% of alterations. The c.137G&gt;T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.Conclusion Our results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance. ER -