A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes.

There are two major cancer susceptibility genes, BRCA1 and BRCA2, mutations in which predispose to early onset breast and ovarian cancer. 2 The frequency of BRCA1 and BRCA2 mutations in the general population ranges from 1-500 to 1-800. 3 In a recent population study, the authors showed that the estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. These frequencies are lower than the frequencies found before. 3 Therefore, the prior probability of finding any person or family with mutations in both the BRCA1 and BRCA2 genes is very low. In the Ashkenazi Jewish population, however, the likelihood of being a carrier of one of the three common BRCA1 or BRCA2 mutations is as high as 1 in 50; this explains why there are multiple reports of double heterozygotes for these mutations. There have been reports of families with two mutations, subjects with two mutations, and families with three mutations in the BRCA genes, mostly in the Ashkenazi Jewish population. To date, only a few subjects or families have been reported to have more than one non-Ashkenazi BRCA mutation. There are five reports describing families that harbour two BRCA1 or one BRCA1 and one BRCA2 mutation. 12–14 We report the first Spanish breast cancer family where two independent mutations, one in BRCA1 and the second in BRCA2, are present in multiple members of a single sibship. The two mutations were found in many subjects. Analysis of the pedigree showed a spectrum of cancer phenotypes associated with one or two mutations, as well as different ages of onset of the cancer.