MicroRNA (miRNA) plays an important role in tumorigenesis, but whether miRNA is a cancer predisposition factor or not is still unknown. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis, we screened genetic variants in 17 selected miRNA genes, which are predicted to regulate key breast cancer genes, in 42 patients with familial breast cancer. Seven novel genetic variants were observed in 7 primary or precursor miRNA genes. Among them, 1 rare variant in the precursor of miR-30c-1 and 1 rare variant in the primary precursor of miR-17 were only observed in noncarriers of BRCA1/2 mutations. In functional assays, these 2 variants resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-30c-1 and miR-17. In the target in vitro assay, we observed that miR-17 could bind to the 3'UTR of BRCA1 mRNAs, which is predicted to be a target for miR-17. Our findings suggest that functional genetic variants in miRNA genes can potentially alter the regulation of key breast cancer genes. Whether they confer genetic susceptibility to breast cancer remains to be determined.