Clinical Significance

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BRCA1 (Online Mendelian Inheritance in Man [OMIM; database online] #113705) and BRCA2 (OMIM #600185) mutations predispose female carriers to a high lifetime risk of breast cancer (>80%) and ovarian cancer (40-65% for BRCA1 carriers and 20% for BRCA2 carriers). The clinical features and management of HBOC syndrome have been reviewed.57 Average ages of breast and ovarian cancer onset are generally younger for BRCA1 carriers than for BRCA2 carriers, but each can manifest as breast cancer in the 20s. BRCA2 contains an ovarian cancer cluster region (OCCR) in exon 11 defined by nucleotides 4075-6503 that appears to convey higher ovarian cancer risks; this region includes the 6174delT Ashkenazi Jewish founder mutation. Penetrance estimates have varied widely among studies, reflecting differences in populations and in study methods.58 Generally, lower penetrance estimates have been seen in studies of the three Ashkenazi Jewish founder mutations. However, in a study of Ashkenazi Jewish probands selected on the basis of having incident primary invasive breast cancer, King et al. found pene-trance estimates (to age 80 years) similar to that described in other groups: 82% for breast cancer for BRCA1 and BRCA2 carriers, 54% for ovarian cancer for BRCA1 carriers, and 23% for ovarian cancer for BRCA2 carriers.59

Male breast cancer is seen in excess in BRCA1 and BRCA2 families, with about two thirds of positive cases involving BRCA2 and one third involving BRCA1.16 Lifetime risk of breast cancer is about 6% for male BRCA2 carriers and is probably lower for male BRCA1 carriers. BRCA2 carriers also are at excess risk for pancreatic cancer.

Many effective cancer risk-management strategies are available for BRCA1 and BRCA2 carriers, as well as for families with a high clinical suspicion of genetic predisposi-tion.60 The chief value of genetic testing is to confirm the need for medical interventions, particularly those that are irreversible such as prophylactic mastectomy and prophylactic oophorectomy. As well, a true negative result (i.e., in the setting of a known familial mutation) obviates the need for aggressive surveillance and prevention measures, and provides reassurance to the person tested as well as to their offspring. Surveillance and management for HBOC syndrome is summarized by Lynch et al.57 and includes consideration of chemoprevention of breast (e.g., tamoxifen) and ovarian (e.g., oral contraceptives) cancers, MRI surveillance for breast cancer under a research protocol, and early breast cancer surveillance (age 25 years) in at-risk female relatives.

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