Monoallelic BRCA1/2 variants in pediatric, adolescent, and young adult patients with central nervous system tumors

Background: Alterations in the BRCA1 DNA repair associated (BRCA1) and BRCA2 DNA repair associated (BRCA2), two key DNA repair genes, are strongly linked to adult-onset malignancies and play a significant role in tumor development. Although BRCA1 and BRCA2 are firmly recognized as hereditary cancer risk genes in adult populations, their role in central nervous system (CNS) tumor susceptibility in younger patients is still debated. Materials and methods: We analyzed 367 pediatric, adolescent, and young adult (AYA) patients with primary CNS tumors. Tumors were classified according to the WHO Classification of Tumors of the CNS, fifth edition. All patients underwent clinical exome sequencing, including BRCA1 and BRCA2. Results: Rare germline BRCA1/2 variants were identified in 17 of 367 patients (4.6%). Among them, 5 patients (1.4% of the overall cohort) carried pathogenic or likely pathogenic variants, whereas 12 patients (3.3%) carried variants of uncertain significance (VUSs). Conclusion: Our findings are consistent with emerging evidence suggesting that monoallelic pathogenic BRCA1/2 variants may act as low-penetrance susceptibility factors in pediatric and AYA CNS tumors rather than as primary oncogenic drivers. Interpretation is limited by cohort heterogeneity, lack of a noncancer control group, and absence of systematic somatic analyses to assess biallelic inactivation or homologous recombination deficiency. Nevertheless, these data support the inclusion of BRCA genes in germline testing panels for pediatric and AYA CNS tumors, with relevant implications for genetic counseling and long-term surveillance.