PROJECT SUMMARY Women with a BRCA1/2 gene mutation (i.e., BRCA1/2 carriers) are at increased risk for hereditary breast and ovarian cancer. However, cancer risk estimates for these individuals are currently wide-ranging and non- specific. BRCA1/2 carriers must make challenging decisions about cancer risk management options (e.g., surveillance, prophylactic surgery); these decisions are complicated by substantial scientific uncertainty regarding their future cancer risks. The opportunity exists to mitigate some of the uncertainty regarding future cancer risks faced by BRCA1/2 carriers. Medical genetics research has identified a set of genetic variants (i.e., small nucleotide polymorphisms, or SNPs) that modify and contribute to cancer risk among BRCA1/2 carriers. By incorporating these genetic risk modifiers into a clinical genetic testing panel, it will be possible to generate a polygenic risk score (PRS) that could allow healthcare providers to more precisely predict BRCA1/2 carriers? cancer risks. However, it is unclear how BRCA1/2 carriers will ultimately perceive or respond to genetic risk modifier test results, because this complex risk information requires an understanding of gene-gene interactions, is supported by a small but growing body of scientific evidence, and remains probabilistic in nature. Psychological research demonstrates that such ambiguous health information can have distinct, and often adverse, effects on people?s decisions, cognitions, emotions, and behaviors. Thus, although we predict that genetic risk modifier testing will aid BRCA1/2 carriers? risk management decision-making, research to determine the utility and effects of this novel risk information is critically needed. The objective of the proposed study is to describe and characterize BRCA1/2 mutation carriers? psychological and behavioral responses to genetic risk modifier testing. We will conduct a prospective, observational study wherein women with newly- identified BRCA1/2 mutations will be offered genetic risk modifier testing. Participants (n=195) will complete baseline and 1-week and 6-month post-receipt of modifier results follow-up quantitative assessments of their risk management decision-making, psychological, and behavioral outcomes. Study aims are to determine the effects of genetic risk modifier testing on BRCA1/2 mutation carriers? decisional conflict with respect to their intention to undergo prophylactic mastectomy or to pursue surveillance, examine the effects of different genetic risk modifier test results (i.e., magnitude of the PRS) on BRCA1/2 mutation carriers? psychological and behavioral outcomes, and describe the extent to which BRCA1/2 carriers choose against learning genetic risk modifier test results. This study of the psychosocial and behavioral impact of genetic and genomic information on affected individuals will provide critical insight into how the clinical translation of genetic risk modifier testing affects patient outcomes. Such research can pave the way for genetic risk modifier testing to inform risk stratification and subsequent cancer control activities with the potential for large-scale population benefits consistent with the goals of public health genomics and precision population health.