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BRCA phenocopies or ascertainment bias?
  1. David Goldgar1,
  2. Vickie Venne2,
  3. Tom Conner2,
  4. Saundra Buys2
  1. 1High-Risk Breast Cancer Clinic, Department of Dermatology, University of Utah, Salt Lake City, Utah, USA
  2. 2High-Risk Breast Cancer Clinic, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
  1. Correspondence to:
 David E Goldgar
 PhD, Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, Utah 84132-2409, USA; david.goldgar{at}

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In a recent issue of the Journal of Medical Genetics, Smith et al1 report a significantly higher risk of breast cancer among non-carriers in breast cancer families in which a BRCA1 or BRCA2 mutation had been identified through clinical testing. The authors found an elevated risk of approximately five-fold, which, if true, has considerable implications for the counselling and clinical management of women testing negative for the mutations found in their family.

Until the study of Smith et al,1 the excess of cases observed among such non-carriers had been noted only anecdotally by many in both the clinical and research settings. In this respect, the systematic study of Smith et al was a welcome confirmation of these anecdotal observations. However, there are a number of methodological flaws in the analysis of Smith et al that render their results difficult to interpret. This stems from the fact that the families used in the analysis were not randomly sampled from the population of all potential families with a mutation, but rather had to meet certain eligibility criteria for genetic testing. Furthermore, the decision to attend a specialty oncogenetics clinic very likely depends on the family history of the individual deciding to undergo testing; the more relatives affected with breast cancer (especially diagnosed at an early age), the more likely a person is to seek genetic counselling/testing. This selection of families, whether through self-selection on family history for attending such clinics and/or through eligibility criteria for genetic testing after evaluation of family history, will result in a bias due to under-representation of families with many unaffected individuals. This bias applies to both mutation carriers and non-carriers, resulting in overestimation of both the penetrance and the phenocopy rate. Although it is possible to correct for this ascertainment bias in …

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