Identification of a novel pathogenic variant in PALB2 and BARD1 genes by a multigene sequencing panel in triple negative breast cancer in Morocco.

Pathogenic variants (PVs) in genes have been mainly associated with an increasing risk of triple negative breast cancer (TNBC). The contribution of PVs in non-BRCA genes to TNBC seems likely since the processing of homologous recombination repair of double-strand DNA breaks involves several genes. Here, we investigate the susceptibility of genetic variation of the and non- genes in 30 early-onset Moroccan women with TNBC. Targeted capture-based next generation sequencing (NGS) method was performed with a multigene panel testing (MGPT) for variant screening. Panel sequencing was performed with genes involved in hereditary predisposition to cancer and candidate genes whose involvement remains unclear using Illumina MiSeq platform. Interpretation was conducted by following the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) criteria. PVs were identified in 20% (6/30) of patients with TNBC. Of these, 16.7% (5/30) carried a PV [10% (3/30) in , 6.7% (2/30) in ] and 6.6% (2/30) carried a non- PV. The identified PVs in genes ( c.798_799delTT, c.3279delC, c.1310_1313del, and c.1658T>G) have been reported before and were classified as pathogenic. The identified founder PVs c.798_799del and c.1310_1313delAAGA represented 10% (3/30). Our MGPT allowed identification of several sequence variations in most investigated genes, among which we found novel truncating variations in and genes. The c.3290dup and c.1333G>T variants are classified as pathogenic. We also identified 42 variants of unknown/uncertain significance (VUS) in 70% (21/30) of patients with TNBC, including 50% (21/42) missense variants. The highest VUS rate was observed in (13%, 4/30). Additionally, 35.7% (15/42) variants initially well-known as benign, likely benign or conflicting interpretations of pathogenicity have been reclassified as VUS according to ACMG-AMP. and along with genetic screening could be helpful for a larger proportion of early-onset TNBC in Morocco.