Caucasian family with two independent mutations: 2594delC in BRCA1 and 5392delAG in BRCA2 gene

Germline mutations in two breast cancer susceptibility genes, BRCA1 and BRCA2, predispose individuals to early onset breast and ovarian cancer. The frequency of mutations in these genes in the general population is very low. Therefore, the prior probability of finding any family with mutations in both genes is even lower. This study reports the presence of two mutations, one in BRCA1 and a second in BRCA2, in a single family with variable expression. The BRCA1 mutation, 2594delC, was identified first in the proband. Analysis on a related family member with early onset bilateral breast cancer for the same mutation was negative. Further analysis on the same individual led to the identification of a second germline mutation, 5392delAG in BRCA2 gene in this family. Without the knowledge of the second mutation in this family, many asymptomatic individuals would have been given a negative test result and be falsely reassured. Further analysis reveals differential expression of the two mutations. The spectrum of cancers as well as the age of onset is variable between the mutations and the generations. Finally, the study exemplifies the fact that molecular analysis of a genetically heterogeneous disease can be very complex and requires a team effort of the patients and their family members, genetic counselors or referring physicians as well as the personnel from the testing laboratory. © 2001 Wiley‐Liss, Inc.