Genome sequencing enhances the diagnostic yield and expands the genetic landscape of male breast cancer.

Purpose: To understand the broader genetic landscape of male breast cancer (MBC), focusing on the utility of genome sequencing (GS) beyond (HGNC: 1100, 1101) variants.

Methods: Twenty-four patients with MBC underwent a multistep genetic analysis. Initial screening targeted variants followed by GS to identify pathogenic/likely pathogenic germline variants through a 3-tiered classification. Polygenic risk score analysis was further incorporated using a model for female breast cancer with 2666 noncancer controls. Exome sequencing was used to transition from germline to somatic investigations, assessing second-hit variant and mutational signatures.

Results: The GS analysis unveiled previously unrecognized pathogenic/likely pathogenic germline variants in , , , and (HGNC: 952, 882, 20473, 16627) among 21 negative patients with MBC, elevating the diagnostic yield from 12.5% to 33.0% in all MBC. Elevated average polygenic risk score was noted compared with controls, with a significant correlation to early-onset MBC when combined with high-penetrance germline pathogenic variants ( 1.10 × 10). Exome sequencing analysis further identified significant somatic oncogenic drivers and revealed a dominant mutational signature SBS3 across negative samples, reinforcing the contribution of omologous recombination deficiency underlying the MBC development.

Conclusion: Our findings extended the MBC genetic spectrum beyond BRCA1/2 and highlighted the intricate interplay of monogenic and polygenic predispositions, presenting a comprehensive MBC genomic profile.