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We hypothesized that aberrant gene silencing by miRNA may affect mutant BRCA penetrance. To test this notion, frequency of single nucleotide polymorphisms (SNPs; n = 42) within predicted miRNA binding sites or miRNA precursors were determined and compared in 363 BRCA1 mutation carriers: asymptomatic (n = 160), breast cancer (n = 140) and ovarian cancer (n = 63) patients, and in 125 BRCA2 mutation carriers: asymptomatic (n = 48), breast cancer (n = 58) and ovarian cancer (n = 19) patients. Overall, 16 of 42 SNPs were polymorphic, 11 had a minor allele frequency greater than 5% and 9 of them maintained the Hardy-Weinberg Equilibrium. Based on Cox regression and Kaplan–Meier analyses, statistically significant differences were noted in BRCA2 mutation carriers by health status in 3 SNPs: CC homozygosity at rs6505162 increased ovarian cancer risk (RR 2.77; p = 0.028; 95% CI, 1.11–6.9); heterozygote SNP carriers of rs11169571 had an ˜2 fold increased risk for developing breast/ovarian cancer, whereas heterozygotes of the rs895819 SNP had an ˜50% reduced risk for developing breast/ovarian cancer. This study provides preliminary evidence for another regulatory level of penetrance of deleterious mutations in cancer predisposition genes.