Characterisation of heterozygous <i>PMS2</i> variants in French patients with Lynch syndrome.

Abstract

Heterozygous germline <i>PMS2</i> 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 <i>PMS2</i> gene in LS. We report 200 <i>PMS2</i> heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5. Genomic rearrangements account for 18% of alterations. The c.137G>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 <i>PMS2</i> variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis. Our results provide further insight into the role of the <i>PMS2</i> gene in LS. While <i>PMS2</i> 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.