Novel variants of unknown significance in the PMS2 gene identified in patients with hereditary colon cancer

Raffaella Liccardo,¹ Carlo Della Ragione,² Nunzio Mitilini,² Marina De Rosa,¹ Paola Izzo,¹ Francesca Duraturo<sup>1

1</sup>Department of Molecular Medicine and Medical Biotechnologies, School of Medicine, University of Naples “Federico II”, Naples, Italy; ²UOC Pathological Anatomy, AORN “A. Cardarelli”, Naples, Italy

Background: Lynch syndrome is associated with genetic variants in mismatch repair (MMR) genes. Pathogenic variants in the MLH1 and MSH2 genes occur in most families in which the phenotype is highly penetrant. These testing criteria are likely to miss individuals with Lynch syndrome due to the less penetrant MMR genes, such as MSH6, MLH3, MSH3, and PMS2. So far, several mutations in the PMS2 gene have been described as responsible for the clinical manifestation of Lynch syndrome. Recent data have reported that families with atypical Lynch phenotype were found to have primarily monoallelic mutations in the PMS2 gene.
Methods: We analyzed the PMS2 gene to detect mutations in members of 64 Lynch syndrome families by direct sequencing.
Results: We report the identification of several genetic variants in patients with LS, of which three are novel variants. The carriers of these novel variants were also carried of other variants in PMS2 gene and/or in other MMR genes.
Conclusion: Therefore, we think that these novel PMS2 variants may act in additive manner to manifestation LS phenotype.

Keywords: Lynch syndrome, PMS2 gene, MMR genes, PMS2 variants, synergist effect of MMR variants