Establishing the role of hypomorphic BRCA1 and BRCA2 variants in cancer risk, etiology and response to therapy

Germline pathogenic variants (PVs) in BRCA1 and BRCA2 are associated with increased risks of breast, ovarian, prostate and pancreatic cancer. Identification of PVs in these genes through genetic testing provides early warning of elevated risks for primary and second cancers, qualifies family members for risk assessment, allows for enhanced breast cancer screening with mammography and MRI, prophylactic mastectomy and salping-oophorectomy for risk reduction and treatment of these cancers with Poly-ADP ribose polymerase inhibitors (PARPi). While most variants are currently categorized as pathogenic, benign, or variants of uncertain significance (VUS), we have identified a fourth group composed of variants that partially alter protein function (hypomorphs) and confer reduced risks for breast and other cancers. We refer to these as hypomorphic/reduced penetrance pathogenic variants (RPPVs). We have verified 13 mainly splice site alterations as consensus RPPVs in BRCA1 and BRCA2 in collaboration with hereditary cancer testing laboratories and have verified 70 other missense RPPVs in the BRCA2 DNA Binding Domain (DBD) using a series of functional studies and case-control association studies. In further studies we have identified 152 candidate BRCA1 and 313 candidate BRCA2 hypomorphic variants. Hypomorph/RPPVs represent a new category of cancer risk variants. These variants have significant implications for clinical management because the reduced risk will not qualify carriers for risk reducing prophylactic surgeries or for PARPi treatment. Here we propose large-scale studies of RPPVs to establish that these variants have unique functional and clinical characteristics compared to BRCA1/2 PVs. We will address this hypothesis with three specific aims as follows: Aim 1: To characterize the functional implications of hypomorphic variants in the BRCA1 BRCT and BRCA2 DNA binding domains. We will identify and validate large series of hypomorphic variants using a series of functional assays. Aim 2: To establish the clinical classifications and characteristics of BRCA1/2 hypomorphic variants. We will use very large datasets from clinical testing populations and population-based studies to establish the risks of the various cancers and the cancer phenotypes associated with each hypomorph/RPPV. Aim 3: To characterize breast cancers and normal breast tissues from women with BRCA1/2 RPPVs using genomic and multiplex immunofluorescent imaging technologies. We will analyze the genome landscape of RPPV breast cancers, focusing on allele-specific loss of heterozygosity, homologous recombination deficiency, and somatic variants associated with therapeutic response, including reversion and epistatic mutations. We will also characterize the influence of RPPVs on the tissue microenvironment of normal and tumor tissues. Project Number: 1R01CA304177-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Fergus Couch (+2 co-PIs) | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $741,738 | Activity Code: R01 | Study Section: Cancer Genetics Study Section[CG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366736