Abstract Breast cancer (BC) is a very serious health concern being the second most commonly diagnosed cancer among American women. Although the overall incidence rate of BC in African American (AA) and European American women converged in 2012, AA women are reported to have a higher mortality rate at every age, and a higher incidence rate under the age of 45, which is a hallmark of hereditary BC. Characteristics of hereditary BC include a family history of the disease, early ages of onset, bilateral BC, male BC, as well as the occurrence of other associated cancers such as ovarian and prostate. Cancer incidences in these families are influenced by inherited risk factors; currently, mutations in known susceptibility genes, including BRCA1/2, explain ~20-30% of hereditary cases, leaving up to ~70% genetically unsolved. Despite the universal need to decipher the currently unexplained cases, it is important to note that these statistics are mainly the result of studying individuals of European descent. The mutational landscape that explains AA hereditary BC is more obscure since, comparatively, it has been vastly understudied. Recognizing this knowledge gap, our group is committed to adding to the current limited resources necessary to better understand AA BC genetics. We are doing this through a strategic community-based recruitment protocol to enroll underrepresented individuals in Alabama, adding to the Alabama Hereditary Cancer Cohort. With over 150 AAs enrolled to date, we have ascertained some impressive AA BC families. Of those families, Family 1CAD is one of the largest with over 15 family members enrolled. Their participation was fostered through an invitation to their family reunion. There, it was disclosed that a deceased family member had a pathogenic BRCA1 mutation (p.M1796R). Therefore, all participating family members were first screened for the BRCA1 mutation through polymerase chain reactions and Sanger sequencing; interestingly, not all cancer-affected individuals screened positive for this mutation. Therefore, five cancer-affected individuals (three mutation-positive and two mutation-negative) were selected and screened using an exploratory research-based gene panel that targets genes that have been suggested, predicted, or clinically proven to be associated with BC and associated cancers. Firstly, this screening confirmed each individual’s mutation status. It also provided additional insight; for example, all three cancer-affected individuals who have BRCA1 M1796R also share a truncation variant in a candidate gene on the panel, which plays an important role in cell cycle regulation (GeneX). A preliminary analysis using AA BC cases from The Cancer Genome Atlas and ethnic-specific controls from the Exome Variant Server, suggests that truncation variants in GeneX are associated with AA BC risk. We are in the process of validating these findings and determining how this truncation variant modifies risk in BRCA1 mutation carriers. Citation Format: Sophonie Omeler-Fenaud, Madison Bishop, Elizabeth Stallworth, Isaac McNeely, Nancy Merner. Complexities of hereditary breast cancer: Investigating a large African American family [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C041.