Characterisation of heterozygous variants in French patients with Lynch syndrome.

BACKGROUND

Heterozygous germline 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 gene in LS.

METHODS

We report 200 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>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 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 gene in LS. While 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.