Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations

Mutations in two major cancer susceptibility genes, BRCA1 and BRCA2 , predispose to early onset breast and ovarian cancer. Since 1994, genetic testing for germline mutations in these genes has been carried out in many countries in both diagnostic and research settings. Mutation analysis is usually done on the basis of a (family) history of breast or ovarian cancer—for example, (very) early age of onset, multiple affected close relatives, multiple tumours in one patient, and breast cancer in men.1–3 Ethnic background may also play a role in decisions about DNA testing, as in some populations founder BRCA1 or BRCA2 mutations are known to occur at relatively high prevalence (for example, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 in Ashkenazi Jews4). In recent years several families have been described in which more than one BRCA mutation segregated, predominantly involving Ashkenazi Jewish founder mutations. These reports describe families that harbour two pathogenic BRCA1 mutations,5 one BRCA1 and one BRCA2 mutation,6,7,8,9,10,11,12,13,14,15,16,17 or even three pathogenic mutations in BRCA genes.18 Some of these families were uncovered because the index case appeared to carry two (founder) mutations, and only rarely was co-segregation of two different mutations suspected beforehand on the basis of the family history. This has led to the recommendation that one should always test for all three founder mutations in individuals of known Jewish ancestry.19 However, DH has also been reported without prior knowledge of Jewish ancestry.10,12,13,16,17,20 In this paper we present four new cases with mutations in both BRCA1 and BRCA2 and review and update the 30 cases reported in the literature, in order to investigate the phenotypic consequences of double heterozygosity (DH)—that is, the …