Background: Hereditary breast cancers (HBC) represent 5-10% of breast cancer, predominantly due to pathogenic/likely pathogenic (P/LP) variants in the BRCA1 and BRCA2 genes and other high (e.g., PALB2) and moderate (e.g., ATM and CHEK2) penetrance genes. There remains a paucity of data evaluating the role of germline-somatic interactions and possible confounders on breast cancer outcomes. Furthermore, current knowledge about HBC is predominantly defined in the context of European ancestry. We sought to characterize differences in clinicopathological features and somatic mutations across P/LP variants in a racially diverse HBC cohort. Methods: Among females with breast cancer and a confirmed P/LP variant in BRCA1, BRCA2, PALB2, CHEK2, and/or ATM currently enrolled through existing Vanderbilt-based studies (ICARE: Inherited Cancer Registry and BEST: Black Women: Etiology and Survival of Triple Negative Breast Cancers (TNBC)), we abstracted data from medical records and performed tumor sequencing using the Tempus xT assay (a 596-gene DNA next-generation sequencing panel and whole-transcriptome RNA sequencing). Interim differences in clinicopathological features were analyzed using Pearson’s chi-square test and the frequency of somatic mutations reported by gene. Results: To date, we have data from 91 females with breast cancer (77% White and 23% Black) and a P/LP variant (36 BRCA1, 27 BRCA2, 13 PALB2, 11 CHEK2 and 4 ATM). The median age at diagnosis was 44 (38-50), 85% had localized breast cancer (Stage I-II), and 69% had Grade 3 tumors. Significantly more Black participants were BRCA1 carriers (p = 0.008), with no significant racial differences observed in other genes. There were significant differences in IHC subtype by gene (p < 0.001); with higher frequency of TNBC in BRCA1 carriers (64%) whereas BRCA2, PALB2, CHEK2, and ATM carriers were more likely to have HR+, HER2- breast cancer (67%, 54%, 73%, 75%, respectively). Of the 85% who received chemotherapy, significantly higher rates were observed in BRCA1 carriers (p = 0.02). Most participants opted to proceed with a risk reducing mastectomy (69%) with no difference across genes (p = 0.91). Higher rates of somatic TP53 mutations were observed among BRCA1, BRCA2, PALB2 carriers (89%, 56%, 46%) but not as frequent among ATM (25%) and CHEK2 (9%) carriers. Conclusions: These preliminary results show that among a diverse cohort of females with HBC, BRCA1 mutations were overrepresented among Black females and those with TNBC. BRCA1, BRCA2, and PALB2 carriers had a higher prevalence of somatic TP53 mutations, which are typically associated with more aggressive tumor biology and worse survival outcomes. Current efforts underway include full genomic and transcriptomic analysis, through which we will be able to improve our understanding of breast cancer clinicopathological characteristics and survival outcomes among a diverse cohort of females with HBC.