Two recurrent pathogenic/likely pathogenic variants in PALB2 account for half of PALB2 positive families in Slovenia

Abstract Background The prevalence and spectrum of PALB2 pathogenic/likely pathogenic variants (PV/LPVs) may vary across different regions, and these have not yet been analysed and reported in Slovenian HBOC families. Methods We performed a retrospective analysis of all 5099 consecutively tested individuals from 4610 families who fulfilled national criteria for HBOC-panel testing from January 2015 to January 2022. After genetic counselling, genetic testing with next generation sequencing was performed for all probands and cascade testing was offered to their blood relatives. Results Among all probands tested 0.9% (40/4610) were PALB2 PV/LPV carriers. 13 different PALB2 PV/LPVs were detected, one of them was novel. Four PV/LPVs were found to be recurrent in Slovenian population with two most frequent being c.509_510del and c.1451T > A. Altogether, 60 individuals from 40 PALB2 positive families were identified, 42 being cancer patients. 28.6% PALB2-positive cancer patients were diagnosed with more than one malignant tumour. We identified three double heterozygote carriers with additional PV/LPVs in ATM, CHEK2 and BRCA1. Discussion This report provides the first comprehensive description of molecular and clinical characteristics of PALB2 carriers in Slovenia. The frequency of PALB2 pathogenic variants in the Slovenian HBOC accounts for 0.9% of all individuals tested for PVs in HBOC-related genes. Our study adds a novel recurrent mutation, which is unique to the Slovenian context and one PV/LPV, which had not been reported in the literature so far. The results of our study add information on genotype and phenotype in PALB2-positive patients and may be used for population specific assessment.