Large genomic rearrangements in germline BRCA1/2 pathogenic variant architecture across tumor types.

e22636 Background: Germline BRCA1/2 pathogenic variation is structurally heterogeneous, comprising small sequence variants and large genomic rearrangements that differ in their genomic architecture and biological consequences. Real-world data defining the contribution of these variant classes across BRCA genes and tumor types remain limited. Methods: We analyzed germline BRCA1/2 findings from 3,248 individuals undergoing comprehensive hereditary cancer testing for small sequence variants (single nucleotide variants and short insertions/deletions) and large genomic rearrangements (deletions and duplications) using a multigene panel. Pathogenic and likely pathogenic variants were classified using standard criteria and evaluated by gene, variant class, tumor type, and clinical actionability. Results: Overall, pathogenic or likely pathogenic BRCA variants were identified in 8.9% (288/3,248) of individuals. Small sequence variants were identified in 258 individuals, while large genomic rearrangements were identified in 39 individuals, with 9 individuals harboring both variant types. At the cohort level, this corresponds to approximately one pathogenic BRCA large genomic rearrangement per 83 individuals analyzed. Among BRCA -positive cases, 58% (167/288) involved BRCA1 and 42% (122/288) involved BRCA2 , with one individual carrying pathogenic variants in both BRCA1 and BRCA2 . Variant-level analysis revealed that large genomic rearrangements were more frequent in BRCA1 than BRCA2 (15.2% vs 10.2%), with deletions predominating over duplications (82.1% vs 17.9%). BRCA pathogenic variants demonstrated marked enrichment in ovarian cancer (16.1%, 77/477), compared with breast (7.7%, 118/1,541), prostate (4.4%, 11/250), and pancreatic cancers (4.1%, 15/362).Large genomic rearrangements were also most prevalent in ovarian cancer (2.1%), compared with breast (1.0%), prostate (0.8%), pancreatic (0.6%), indicating relative enrichment of rearrangements in ovarian tumors. Pathogenic variants in cancer predisposition genes were identified in 14.6% (475/3248) of individuals, with non- BRCA genes accounting for 41.7% of findings. Overall, 12.1% of individuals harbored germline alterations with direct therapeutic relevance including eligibility for PARP inhibitor therapy. Conclusions: Large genomic rearrangements constitute a non-trivial component of germline BRCA pathogenic variation, show preferential involvement of BRCA1 , and demonstrate enrichment in ovarian cancer, consistent with HRD-driven tumor biology. Together, these findings provide population-level insight into pathogenic germline alterations across BRCA and other therapeutically relevant hereditary predisposition genes, underscoring the broader relevance of inherited cancer susceptibility in informing targeted and immunotherapy strategies within precision oncology.