JOURNAL ARTICLE
MULTICENTER STUDY

Validity of models for predicting BRCA1 and BRCA2 mutations

Giovanni Parmigiani, Sining Chen, Edwin S Iversen, Tara M Friebel, Dianne M Finkelstein, Hoda Anton-Culver, Argyrios Ziogas, Barbara L Weber, Andrea Eisen, Kathleen E Malone, Janet R Daling, Li Hsu, Elaine A Ostrander, Leif E Peterson, Joellen M Schildkraut, Claudine Isaacs, Camille Corio, Leoni Leondaridis, Gail Tomlinson, Christopher I Amos, Louise C Strong, Donald A Berry, Jeffrey N Weitzel, Sharon Sand, Debra Dutson, Rich Kerber, Beth N Peshkin, David M Euhus
Annals of Internal Medicine 2007 October 2, 147 (7): 441-50
17909205

BACKGROUND: Deleterious mutations of the BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. At least 7 models for estimating the probabilities of having a mutation are used widely in clinical and scientific activities; however, the merits and limitations of these models are not fully understood.

OBJECTIVE: To systematically quantify the accuracy of the following publicly available models to predict mutation carrier status: BRCAPRO, family history assessment tool, Finnish, Myriad, National Cancer Institute, University of Pennsylvania, and Yale University.

DESIGN: Cross-sectional validation study, using model predictions and BRCA1 or BRCA2 mutation status of patients different from those used to develop the models.

SETTING: Multicenter study across Cancer Genetics Network participating centers.

PATIENTS: 3 population-based samples of participants in research studies and 8 samples from genetic counseling clinics.

MEASUREMENTS: Discrimination between individuals testing positive for a mutation in BRCA1 or BRCA2 from those testing negative, as measured by the c-statistic, and sensitivity and specificity of model predictions.

RESULTS: The 7 models differ in their predictions. The better-performing models have a c-statistic around 80%. BRCAPRO has the largest c-statistic overall and in all but 2 patient subgroups, although the margin over other models is narrow in many strata. Outside of high-risk populations, all models have high false-negative and false-positive rates across a range of probability thresholds used to refer for mutation testing.

LIMITATION: Three recently published models were not included.

CONCLUSIONS: All models identify women who probably carry a deleterious mutation of BRCA1 or BRCA2 with adequate discrimination to support individualized genetic counseling, although discrimination varies across models and populations.

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