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The PMS2 gene is one of the DNA mismatch repair genes (MMR) implicated in Lynch syndrome (LS). A subset of PMS2 pathogenic variants (PVs) are splice variants mostly affecting canonical GT/AG splicing sequences. However, the majority of the intronic variants outside canonical splice sites remained as variants of unknown significance, even though some of them would alter the splicing process. In this report, we describe the analysis of such an intronic variant (c.251-5T C) detected in an 82-year-old patient diagnosed with endometrial cancer displaying microsatellite instability and the loss of PMS2 expression displayed. RNA analysis demonstrated that this variant lead to the complete exon 4 skipping, resulting in the synthesis of a truncated protein. This finding shows the relevance of functional RNA analysis in the non-canonical intronic variant assessment and the importance of systematic evaluation of MSI/loss of expression of MMR genes for LS screening in patients with endometrial cancers.

Patients with tumors displaying high microsatellite instability (MSI-H) but no germline MMR inactivation are suspected for Lynch-like syndrome (LLS). To explore the involvement of acquired somatic MMR alteration as a cause, we screened 113 patient tumor samples for MMR gene variations and loss of heterozygosity. Somatic MMR alterations were found in 85.8% of patients including "double hits" in 63.7% of patients, mainly diagnosed with colon and endometrial cancers. Interestingly, 37.5% of them were under the age of 50, and seven patients were under 30. Somatic alterations were mainly attributed to the MLH1, MSH2 genes, likely reflecting the functional importance of these key MMR genes. Pathogenic variants co-existed in other cancer genes in particular the APC gene displaying a characteristic MMR deficiency-related "mutational signature", indicating that it may be inactivated owing to MMR deficiency. We speculated that APC inactivation could trigger an accelerated malignant transformation underlying early-onset cancers. Our findings provide further insight into the mechanisms underlying LLS, somatic MMR inactivation being a major cause for early-onset LLS through pathways differing from those involved in late-onset sporadic cases.

BackgroundHeterozygous 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.MethodsWe report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.ResultsGenomic 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 PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.ConclusionOur 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.