Abstract Background: Somatic mutation signatures may represent the footprints of genetic and environmental exposures that cause different types of cancer. However, few studies have comprehensively examined the association between germline variants and somatic mutation signatures, and none in African ancestry populations. Methods: Study samples consist of 1,011 breast cancer patients from The Cancer Genome Atlas (TCGA; 168 Black, 737 White, and 106 other ancestries, discovery set) and 170 Nigerian women with breast cancer (validation set). SomaticSignatures was employed to extract mutation signatures from whole-genome or whole-exome sequenicng data, and to estimate contributions of signatures on each sample. SNPtest and SKAT-O were used to conduct association tests for the association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants. SNP array-based heritability was calculated by GCTA. Results: Nine stable signatures were inferred in total. Four of them – APOBEC C>T, APOBEC C>G, aging, and homologous recombination deficiency (HRD) – were highly similar to known COSMIC signatures. These together explained the vast majority (60%~85%) of mutation signature contributions regardless of race/ethnicity or tumor subtype. The heritability estimates displayed significantly heritable components for APOBEC C>T signature (h2 = 0.575, P = 0.010) and combined APOBEC signature (h2 = 0.432, P = 0.042). In TCGA dataset, seven common SNPs on/near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21~0.45) of APOBEC signature contribution at genome-wide significance, while rare deleterious variants in MTCL1 and HIV-EP1 were also significantly associated with this signature contribution (P =1.9×10-6, 2.2×10-5, respectively). The combined rare deleterious variants in BRCA1 and BRCA2 were significantly correlated with the contribution of HRD signature (P =1.0×10-8, 1.1×10-5, respectively). In the Nigerian cohort, only the associations in HIV-EP1 and BRCA2 were replicated with relatively higher mutation frequencies (N = 9, 8; P = 0.05, 0.01, respectively). In addition, the combined rare deleterious variants in HRD pathway genes was significantly associated with the contribution of HRD signature in both TCGA (P = 2.8×10-5) and Nigerian samples (P = 0.01). After excluding BRCA1/2, this association turned to be nonsignificant. Conclusion: Our study identified associations between germline variants and mutational patterns in breast cancer across different ethnicities, especially in African women for the first time. This finding has important public health implications as it provides evidence to substantiate causal links between germline genetic variants and carcinogenesis process. Further replications in larger and diverse populations are needed. Citation Format: Shengfeng Wang, Jason J. Pitt, Yonglan Zheng, Toshio F. Yoshimatsu, Guimin Gao, Markus Riester, Ayodele Sanni, Olayiwola Oluwasola, Dominic Fitzgerald, Temidayo Ogundiran, Chinedum Babalola, Abiodun Popoola, Adeyinka Falusi, Wendy Winckler, John Obafunwa, Oladosu Ojengbede, Nasiru Ibrahim, WABCS Working Group, Jordi Barretina, Kevin P. White, Dezheng Huo, Olufunmilayo I. Olopade. Germline variants and somatic mutation signatures in breast cancer across populations of African and European ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 287.