Honing in on BRCA Genetic Testing

Abstract & Commentary

Synopsis: BRCA mutation testing is useful in identifying individuals at risk for breast and ovarian cancers due to mutations in those genes. However, gene sequencing is expensive and is associated with potential legal, psychological, and ethical issues. Thus, efforts are under development to identify those at greatest risk for BRCA mutation for gene testing. In this report, using a series of 148 family pedigrees for which gene testing had been done, the performance of 8 experienced genetic counselors was compared to a computer program (BRCAPRO). Although, with the pedigree data in hand, the counselors were comparably sensitive in prediction of BRCA carrier status, their specificity was not as good as the computer. Thus, computer-assisted evaluations for subsequent gene testing are likely to allow more precise recommendations regarding gene testing for BRCA mutations.

Source: Etthus DM, et al. J Natl Cancer Inst. 2002;94: 944-951.

Genetic counseling can be of great value for families that carry a genetic risk for cancer, such as those who carry BRCA mutations. The purpose of the current report was to compare the performance of 8 genetic counselors with that of a computer model (BRCAPRO) in identifying those families likely to carry a BRCA gene mutation. Eight experienced cancer risk counselors from different cancer center genetics clinics estimated BRCA gene mutation probabilities for 148 pedigrees that were selected because of a perceived risk for such mutations including a proband with either breast or ovarian cancer and available unequivocal sequencing data of the BRCA1 and BRCA2 genes. In this selected group, 43% were positive for BRCA mutations. Genetic counselors were asked to identify those with a greater than 10% BRCA gene mutation probability. Using that threshold, the sensitivity for identifying carriers was 94%, which compared favorably with the computer program (that scored a sensitivity of 92%). However, median specificity at this threshold was 16% for the risk counselors and 32% for the computer (P = .04). Thus, sensitivity for identifying BRCA gene mutation carriers was similar for risk counselors and the computer program, but the computer model consistently demonstrated superior specificity and was overall better at discriminating BRCA carriers from noncarriers.

Comment by William B. Ershler, MD

Women who inherit certain mutations within the BRCA1 or BRCA2 genes face a 35-85% lifetime risk of developing breast cancer1,2 and a 16-57% chance of developing ovarian cancer.3 Genetic counseling and medical or surgical interventions are likely to reduce these risks. One element of the genetic counseling consultation is the identification of those truly at increased risk. Gene testing is costly and may be complicated by social and legal issues. Thus, screening efforts performed by professionals knowledgeable in the limitations and interpretations of such tests is warranted. This is highlighted by a recent ASCO policy statement that suggests that BRCA gene mutation screening be limited to individuals whose probability for carrying a mutation is at least 10%.4 The problem, of course, is to identify those characteristics that impart that 10% risk.

The current research suggests that genetic counselors do a pretty good job at this inasmuch as their interpretation of the pedigrees and clinical data of the sample population (148 families in this report), using a 10% probability threshold, led to a sensitivity level of 94% for identifying carriers. However, specificity was considerably lower than that of the computer (16% vs 32%). Thus, the BRCAPRO program results in the recommendation of gene testing for fewer families. This program, and other related programs, are available on the internet by searching for "BRCAPRO."

Genetic counseling, of course, involves much more than screening for those to be tested by sequencing of the BRCA genes. Counselors are critical, not only for their recommendations for screening, but also for education and interpretation of the results and for discussing the management of cancer risks. The BRCAPRO computer program is a useful tool for assisting in the overall process.

Dr. Ershler of INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, D.C.


1. Easton DF, et al. Am J Hum Genet. 1995;56:265-271.

2. Antoniou AC, et al. Genet Epidemiol. 2000;18:173-190.

3. Struewing JP, et al. N Engl J Med. 1997;336:1401-1408.

4. ASCO Genetics testing statement. http://www.asco.org.