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Introduction. Over the past several years, common genetic variants, usually with minor allele frequency (MAF) > 5%, in approximately 70 loci have been identified as breast cancer risk factors via genome-wide association studies (GWAS). There are very few data on these associations in Spanish populations. We used data from the Breast Oncology Galicia Network (BREOGAN) study to assess 67 low MAF coding variants in GWAS-identified loci regions for their association with breast cancer risk, including main effects and stratifications by ER status, tumor grade, and presence/absence of axillary lymph nodes. Methods. The study included 1407 invasive breast cancer cases diagnosed between 1997 and 2013 in the Hospital Universitario de Santiago (CHUS) and Vigo (CHUVI), and 1806 neighborhood matched controls. Multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). SNP genotyping was done by MALDI-TOF based on MassArray® (SEQUENOM) y iPLEXTM Gold technology in the CeGen, National Genotyping Center in the Galician Foundation of Genomic Medicine. Results. A total of six variants were associated with breast cancer risk at P < 0.05, after adjustment for the corresponding index SNP, while five variants were associated at P < 0.01. SNPs rs2981579 and rs2981582 in the FGFR2 gene were associated with decreased risk with ORs of 0.66 (95% CI, 0.60 - 0.73 [P = 3.45 × 10-12]) and 0.69 (95% CI, 0.63 - 0.77 [P = 7.5 × 10-9]), respectively. The rs10941679 variant at 5p12 was associated with lower risk (OR = 0.83; 95% CI, 0.74 - 0.92; P = 0.00365) and SNP rs11199914 at 10q26.12 was associated with 1.37-hold elevated risk (95% CI, 1.08 - 1.72; P = 0.03372). Variant rs12422552 at 12p13.1 was associated with decreased risk (OR = 0.61; 95% CI, 0.47 - 0.79 [P = 0.00071]) while SNP rs12493607 in the TGFBR2 gene was associated with decreased risk (OR = 0.80; 95% CI, 0.70 - 0.92 [P = 0.00958]). In tumor subtype analyses, SNPs rs2981579 (P = 4.2968 × 10-12), rs2981582 (P = 1.6999 × 10-8) in the FGFR2 gene, rs0941679 at 5p12 (P = 0.0038), rs12422552 at 12p13.1 (P = 0.00380), and rs10941679 in the MRPS30 gene (P = 0, 00380) were associated with decreased risk of ER+ breast cancer. Only SNPrs4245739 in the MDM4 gene was found to be associated with ER- breast cancer (P = 0.0010). Stratification by tumor grade showed that SNPs rs2981579 and rs2981582 in the FGFR2 gene were associated with decreased grade 3 breast cancer risk (P = 0.02741393 and 0.03688523, respectively). Conclusion. We identified associations of variants flanking the known susceptibility loci with breast cancer risk in a Spanish population, with evidence of etiologic heterogeneity by tumor subtype and grade. These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Citation Format: Manuela Gago-Dominguez, Maite Peña, Maria Torres, Jose L. Soto-Vázquez, Miguel E. Aguado-Barrera, Sara Miranda, Manuel Calaza, Alejandro Novo, Victor M. Muñoz, Angel Carracedo, M. Elena Martinez, J. Esteban Castelao. Genetic susceptibility to breast cancer in a Spanish population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2781. doi:10.1158/1538-7445.AM2015-2781