BRCA1/BRCA2 Germline Mutations and Breast Cancer Risk

Definition

Mutations in the breast cancer genes BRCA1 and BRCA2 cause elevated risks to breast cancer and ovarian cancer. BRCA1 maps to chromosome 17 (band q21); BRCA2 maps to chromosome 13 (band q12).

At the genetic level there are interesting analogies between the two genes, even though they are not detectably related by sequence. Both genes are large (coding regions of 5.6 and 10.2 kb, respectively), complex (22 and 26 coding exons, respectively), and span about 80 kb of genomic DNA. Both have extremely large central exons encoding >50% of the protein. The majority of the mutations in both genes detected to date lead to premature termination of protein translation, presumably resulting in an inactive truncated protein. Gene changes are distributed nearly ubiquitously over the coding exons and immediate flanking introns. Even though more than half of all mutations are found only once, many mutations have been detected repeatedly in certain populations. For most of these, this has...