Federal Project Grant Award Summary

Mayo Clinic has been awarded $741,738 by the National Cancer Institute under the Cancer Cause and Prevention Research program (CFDA 93.393) for a five-year project (June 1, 2026–May 31, 2031) investigating hypomorphic BRCA1 and BRCA2 variants and their role in cancer risk and treatment response. The research will establish the functional and clinical characteristics of reduced penetrance pathogenic variants (RPPVs)—a newly identified category of cancer risk variants that confer reduced disease susceptibility compared to pathogenic variants. The project will deliver large-scale functional and clinical studies characterizing 465 candidate hypomorphic variants identified in BRCA1 and BRCA2, with particular focus on splice site alterations and missense variants in the DNA binding domain. Research outputs will include functional characterization studies, case-control association analyses, and evidence establishing whether these variants warrant distinct clinical management protocols separate from standard pathogenic variant guidance regarding prophylactic surgeries and poly-ADP ribose polymerase inhibitor treatment eligibility.

The project addresses a critical gap in precision oncology by developing clinical evidence to differentiate hypomorphic variants from pathogenic variants, with significant implications for genetic counseling, cancer risk stratification, and therapeutic decision-making among carriers. Deliverables will advance the scientific understanding of variant-specific cancer mechanisms and inform clinical laboratory classification standards for hereditary cancer testing, supporting improved patient care and risk management strategies within the hereditary cancer community.