Inheritance is believed to play a major role in 5-10% of breast cancer. The breast cancer susceptibility genes BRCA1 and BRCA2 are estimated to account for more than half of these cases. Recent studies have suggested that breast cancers associated with BRCA1 germline mutations are of higher grade than sporadic cases. The purpose of this investigation was to determine if there are significant pathologic and biologic differences between hereditary BRCA2 related breast carcinomas and non-hereditary breast cancers. Forty cases of hereditary breast cancer from families associated with a specific 999del5 BRCA2 mutation were compared with regard to histologic and biologic factors to an age matched control group. Thirty-four patients (85%) had ductal carcinoma, two had lobular carcinoma, and one patient had medullary carcinoma. Compared to the control group, the BRCA2 tumors had less tubule formation (p = 0.02), more nuclear pleomorphism (p = 0.02), and higher mitotic rates (p = 0.002), and were thus of higher histologic grade (p = 0.003). By flow cytometry the BRCA2 tumors also had significantly higher S-phase fractions than the control tumors (p = 0.02). Significant differences in axillary lymph-node involvement or ploidy status were not detected. According to the results of this study, hereditary breast cancers associated with the 999del5 BRCA2 mutation are high grade tumors with a rapid proliferation rate. Other or additional factors than the defining BRCA2 mutation are involved in determining the tumor type.