Two new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations identified in a cohort of Italian breast and ovarian cancer families.

Double heterozygosity for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. Here we describe genetic and clinical data of two female double heterozygotes for both BRCA1 and BRCA2 mutations found in a cohort of 201 mutated Italian breast/ovarian cancer families out of 942 cases analyzed. The first one is a female patient affected by bilateral breast cancer at 47 and 49 years of age, carrying both a BRCA2 nonsense mutations (c.7408A>T - p.Arg2394X) and a BRCA1 proven splicing defect (IVS5-12A>G or c.331_332ins11 - p.Arg71SerfsX21). The second one is a female patient affected by ductal breast cancer at 42 years of age, carrying both a BRCA1 nonsense mutations (c.3726C>T - p.Arg1203X) and a BRCA2 frameshift mutation (c.3036_3039delACAA - p.Ala938ProfsX21). Although this event is rare (2/201: 1% in our clinical records, consistent with literature data) and the phenotype is not worse than carriers of a single mutation, it has to be considered in the assessment of the biological effect of variants of uncertain biological effect. Furthermore the presence of a second mutation has important consequences for genetic counselling of relatives. We suggest that mutation analysis of index cases should always be extended in order to avoid missing a second BRCA mutation.