ID #449 Prevalence of BRCA1/2 germline variants in pediatric and adolescent/young adult brain tumors
Giada Del Baldo, Selene Cipri, Emanuele Agolini, Antonella Cacchione, Sabrina Rossi, Sabina Barresi, Andrea Carai, Giovanna Stefania Colafati, Luigi Boccuto, Angela MastronuzziAbstract
Background
BRCA1/BRCA2 germline variants are well-established cancer predisposition factors in adults, yet their contribution to central nervous system (CNS) tumor susceptibility in pediatric and adolescent/young adult (AYA) patients remains uncertain. Recent pediatric sequencing studies suggest that heterozygous BRCA2 pathogenic variants may act as low-penetrance susceptibility alleles in selected CNS tumors.
Methods
We retrospectively reviewed 367 pediatric and AYA patients with primary CNS tumors diagnosed between 2011 and 2025 at our center, all of whom underwent clinical exome sequencing including BRCA1 and BRCA2. Variants were classified per ACMG criteria. Segregation was assessed by trio testing when available or by single-parent testing. Somatic sequencing was performed in a subset of cases.
Results
Germline BRCA1/2 variants were identified in 17/367 patients (4.6%). Pathogenic/likely pathogenic (P/LP) variants were detected in 5/17 (29%): four monoallelic truncating pathogenic variants in BRCA2 and one monoallelic likely pathogenic variant in BRCA1. The remaining 12/17 (71%) carried variants of uncertain significance (VUS), including two BRCA1 VUS and multiple BRCA2 VUS, with two patients harboring more than one VUS. Variant-positive cases spanned multiple histologies, including high-grade glioma, low-grade glioma, and medulloblastoma, supporting a non–tumor-type–restricted distribution. Family history of cancer was positive in 8/17 (47.1%). Inheritance assessment was available for most patients (15/17): 64.7% showed maternal inheritance. Tumor sequencing was limited and did not allow systematic evaluation of biallelic inactivation, loss of heterozygosity, or homologous recombination deficiency.
Conclusions
In this large single-center pediatric/AYA CNS tumor cohort, monoallelic BRCA1/2 P/LP variants were uncommon but detectable, with a predominance of truncating BRCA2 alterations across diverse CNS tumor entities. These data are consistent with a model in which heterozygous BRCA variants may function as low-penetrance susceptibility factors rather than primary drivers of tumorigenesis. Inclusion of BRCA1/2 in germline testing panels may inform genetic counseling, cascade testing, and long-term surveillance.