Genetic testing for BRCA1 and BRCA2 mutations - ready for implementation?

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With the discovery of BRCA1 and BRCA2, testing for germline mutations became a possibility. However, there are several questions that must be considered if genetic testing is to be widely implemented. First, who should have the test - are there defined groups at increased risk? Second, is the laboratory technically capable of accurate testing and with what sensitivity and specificity? Are the test results interpretable? Finally, is there clinical utility to the test? That is, are there interventions as a result of the test that will benefit the patient, and do the benefits outweigh the risks?

At least partial answers to these questions are now available. There are well-established methods of identifying mutations, and there are known founder mutations that simplify testing in some populations. In particular, there are data that suggest that screening all Ashkenazi Jewish women for the three founder mutations in this group may significantly reduce deaths from ovarian cancer in this population. Direct sequencing and heteroduplex analysis are both methods with sensitivity well over 90% for coding region and splice site mutations; however, the problem of genomic rearrangements in BRCA1 remains. Variants of uncertain significance remain a problem, particularly in BRCA2, but truncating mutations are clearly associated with a markedly increased risk of breast and ovarian cancer. Perhaps most importantly, recent work is beginning to provide justification for prevention strategies for both breast and ovarian cancer, as well as evidence that genetic testing is well-tolerated psychologically. Finally, most Western countries have addressed the issue of genetic discrimination and offer protection through either nationalized health services or federal legislation. In summary, the past five years have yielded advances in all areas pertaining to genetic susceptibility testing, and the promise of cancer prevention associated with the isolation of BRCA1 and BRCA2 is becoming a reality.