ABSTRACT
More than a decade after the discovery of the BRCA1 and BRCA2 genes, there remains scholarly debate regarding the precise magnitude and spectrum of cancer risks to
individuals carrying mutations of these genes (1-9). The ranges of risk estimates derived
have emerged from different types of studies performed over the past decade, and thus the
ranges of risks reported may reflect the biases of the ascertainment methodologies
employed. Alternatively, or additionally, environmental or other modifying genetic
factors may impact on kindreds, segregating BRCA mutations. Modifying genetic factors may include those intrinsic to the mutation itself, i.e., genotype-phenotype correlations,
as well as extrinsic modifiers due to coinheritance of mutations in other genes. A
significant variance in penetrance estimates conveyed to women at the time of genetic
counseling may pose vexing challenges as they consider the intricacies of treatment
options, including preventive surgeries. This chapter will provide an overview of the
various methods that have been utilized to estimate risk associated with BRCA mutations, will highlight the genotype/phenotype associations that have been observed, and will
review the risk for tumors other than breast and ovarian cancer in carriers of BRCA1/2 mutations. The conclusion that will emerge is that clinicians can draw on a large literature
providing relatively stable estimations of risks tailored to individuals in families affected
by multiple cases of breast or related cancers, or individuals in the general population
lacking evidence of a family history of syndromic cancers.
