ABSTRACT
The incomplete penetrance associated with mutations in BRCA1 and BRCA2 suggests that environmental or genetic risk-modifying factors may exist that affect the phenotype of
BRCA1 and BRCA2 mutation carriers. Initial estimates from clinic-based data indicated that around 80% of carriers of mutations in BRCA1 and BRCA2 from multiple-case families would develop breast cancer (1,2), whereas a later pooled analysis from
population-based studies has suggested that for the great majority of mutation carriers,
their average lifetime risk is closer to 45% to 66% (3). This pooled-analysis of BRCA1 and BRCA2 carriers also showed that in BRCA1 mutation carriers, the breast cancer penetrance for relatives ascertained through a breast cancer case was significantly higher
than for those ascertained through an ovarian cancer case, and even higher if the index
case was diagnosed before the age of 35 (3). Conversely, the ovarian cancer risk was
higher in families ascertained through an ovarian cancer index case. Similar differences
in risk, depending on the cancer site in the index case, were also reported by Simchoni
et al. in an Ashkenazi Jewish population (4). These variations in risk between different
studies, and according to the phenotype of the proband, are consistent with the presence
of modifying factors. There is also a recent report that the phenocopy rate in BRCA1 and BRCA2 families is increased over the population rate, further suggesting the existence of environmental or genetic modifiers (5).
