Abstract Purpose: The aim of the study was to estimate breast cancer risk conferred by individual single-nucleotide polymorphisms (SNPs) of breast cancer susceptibility genes in the monoubiquitinated FANCD2–DNA damage repair pathway. Methods: We selected 48 tagging SNPs (tSNPs) from eight breast cancer susceptibility genes (TP53,PTEN,NBS1,BRIP1,PALB2,ATM,CHEK2 and RAD50) involved in the monoubiquitinated FANCD2–DNA damage repair pathway.The 48 tSNPs were genetyped by SNPscan in 734 women with breast cancer(534 sporadic cases and 200 early-onset and familial cases) and 672 sex- and age-matched healthy controls from Hunan and Sichuan Province of China.The odds ratio were calculated by logistic regression analysis under co-dominant model ,dominant model and recessive model respectively. Results: Forty-five tSNPs were successfully genotyped by SNPscan, and the call rates for each tSNP were above 98.9%. We found that 13 tSNPs of five genes (PALB2, TP53, NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. A total of five tSNPs (rs2299941 of PTEN, rs2735385, rs6999227, rs1805812, and rs1061302 of NBS1) were tightly associated with breast cancer risk in sporadic cases, and five other tSNPs (rs1042522 of TP53, rs2735343 of PTEN, rs7220719, rs16945628, and rs11871753 of BRIP1) were tightly associated with breast cancer risk in early-onset and familial cases. We have not found significant tSNPs in the other three genes (ATM, RAD50, and CHEK2).Three tSNPs of TP53(rs12951053, rs1042522 and rs8064946),three tSNPs of BRIP1(rs16945628, rs7220719 and rs11871753) and rs2735343 of PTEN can significantly increase the risk of breast cancer,and most of these were under the analysis of early-onset and familial cases.Four tSNPs of NBS1(rs2735385, rs6999227, rs1805812 and rs1061302),rs2299941 of PTEN and rs513313 of PALB2 can significantly decrease the risk of breast cancer,and most of these were under the analysis of sporadic cases. Conclusions: Some of the tSNPs of five breast cancer susceptibility genes (PALB2, TP53, NBS1, PTEN, and BRIP1) involved in the monoubiquitinated FANCD2–DNA damage repair pathway were significantly associated with breast cancer risk in women from Hunan and Sichuan Province of China.Some locuses can increase breast cancer risk,and others can decrease breast cancer risk.But the majority of the tSNPs are located in the intron domain and their functions are unknown, so larger studies are needed to research the functions of these genes further. Citation Format: Chen F, Tang L, Huang J. Association analysis of single-nucleotide polymorphisms in FANCD2-DNA damage repair pathway genes with breast cancer risk. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-03.