Exome-based cancer driver gene comprehensive testing can provide a genetic diagnosis for individuals with...

Triple-negative breast cancer (TNBC) is characterized by aggressive behaviour, high tumor heterogeneity, and an increased likelihood of recurrence and early metastasis. These factors hinder successful treatment. Genetic diagnosis enables personalized clinical recommendations and treatment options. The objective of this study was to validate whole-exome sequencing (WES) and variant prioritization in cancer susceptibility genes (CSG) associated with hereditary cancer (HC) predisposition in TNBC patients (n = 24). We present the development of a reproducible bioinformatic pipeline and its technical validation in a validation cohort (n = 25). This cohort comprised individuals with diverse primary tumors who had a previously confirmed molecular diagnosis of a hereditary cancer syndrome, serving as gold-standard cases to assess the pipeline's analytical accuracy. We consolidated a comprehensive panel of cancer genes and determined all variants in the TNBC discovery cohort (12.5% of patients), identifying three pathogenic germline variants (gPV) in ATM, RAD51D, and BRCA1. These genes are involved in the molecular pathway of DNA repair by homologous recombination (HRD). Our results demonstrate that the developed bioinformatic pipeline provides reliable genetic diagnosis of cancer predisposition syndromes from exome data, applicable not only to TNBC patients but also to individuals with any cancer suspected of having a hereditary component.