Breast cancer has a strong heritable component with approximately 15% of patients exhibiting a family history of the disease. My group recently established that inherited variants in 12 genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53) predispose to breast cancer (1, 2), that variants in all 12 genes increase risks of breast cancer in minority populations (3), and that variants in certain genes predispose only to estrogen receptor (ER) positive (ATM and CHEK2) or ER negative and triple negative breast cancer (TNBC) (BARD1, RAD51C and RAD51D) (4-6). Despite these major advances, clinical application of the information is still lacking. In addition, up to 50% of the familial risk of breast cancer remains unexplained. Under this award we plan to address clinically relevant issues, including improved application of genetic testing results for risk management of patients and improved selection of breast cancer therapy. In addition, we aim to identify new breast cancer predisposition genes that account for the missing heritability. The proposed studies are unified under a theme of advancing understanding of predisposition genetics. The studies are as follows: A. Age-specific and population-specific cancer risk assessment for predisposition gene variants. Results from hereditary multigene panel testing has limited clinical utility because only lifetime risk estimates of cancer by age 80 are available. Here we will estimate 5 and 10-year risks of breast cancer, so that patients can make decisions about medical management. In addition, we have evidence that specific genes have much higher penetrance in African Americans. We will determine the penetrance of predisposition gene variants using a large African American cohort study in order to modify risk management guidelines for this population. B. Functional characterization of predisposition gene variants. Variants of uncertain significance (VUS) identified by genetic testing remain a major problem for individuals receiving clinical genetic testing. We aim to combine high-throughput functional analysis of VUS in ATM, BRCA2 and PALB2 genes with genetic data from families in integrated models to determine the clinical relevance of many VUS alterations. C. Therapeutic response for breast cancer predisposition genes. The responsiveness of breast tumors associated with predisposition gene variants to standard or targeted therapy is only known for BRCA1 and BRCA2 mutation carriers. Here we aim to identify all patients with pathogenic variants in the commonly mutated BRCA1, BRCA2, PALB2, ATM and CHEK2 genes from a series of neo-adjuvant, adjuvant and metastatic breast cancer clinical trials and to assess response to therapy and outcome. D. Identification of novel breast cancer predisposition alleles. The common and rare risk alleles for breast cancer account for only 50% of the familial risk in the population. In an effort to identify the missing heritability we will collaborate with Regeneron Inc. through our SIMPLEXO consortium to identify common and rare alleles associated with breast cancer risk in 45,000 breast cancer patients.