Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing

SIMPLE SUMMARY: BRCA1 and BRCA2 are two major high-penetrance breast/ovarian cancer predisposition genes, whose mutations can lead to high risk and early onset of breast and ovarian cancer. Numerous studies are focused on spectrum and prevalence of BRCA1/2 mutations worldwide. This is the first study that exclusively focused on native Apulian probands. We found that ten recurrent BRCA1/2 pathogenic variants account for more than half of the patients with proven HBOC syndrome from Apulia. Besides BRCA1 c.5266dupC, which is present in significant numbers in every Apulian province, the other PVs occur at a high frequency in some areas and not others. In-depth knowledge of the mutation spectrum of the target population and of the relatively small number of recurrent mutations is crucial to develop a specific cost-effective strategy for mutation screening and a program for breast–ovarian cancer control and prevention through more liberal, yet rational, genetic testing and counseling. ABSTRACT: BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype–phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a “founder effect”. Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.