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Determination of Cancer Risk Associated with Germ Line BRCA1 Missense Variants by Functional Analysis

¹ Risk Assessment, Detection, and Intervention Program, and ² Lifetime Cancer Screening and Prevention Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; ³ Centro Federal de Educação Tecnológica de Química; ⁴ Laboratório de Metabolismo Macromolecular Firmino Torres de Castro, Instituto de Biofísica Carlos Chagas Filho, and ⁵ Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; ⁶ Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins University, Baltimore, Maryland; ⁷ Department of Experimental Oncology, Istituto Nazionale Tumori; ⁸ Fondazione Italiana per la Ricerca sul Cancro, Institute of Molecular Oncology, Milan, Italy; ⁹ Department of Haematology and Genetic Pathology, Flinders University Medical Centre, Bedford Park, South Australia, Australia; ¹⁰ Department of Medical Oncology, Fox Chase Cancer Center; ¹¹ Division of Medical Genetics, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; ¹² The Dr. John T. Macdonald Foundation Center for Medical Genetics and Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, Florida; ¹³ Department of Biopharmaceutical Sciences, California Institute for Quantitative Biomedical Research, University of California at San Francisco, San Francisco, California; ¹⁴ Department of Dermatology, University of Utah, Salt Lake City, Utah; and ¹⁵ Mayo Clinic College of Medicine, Rochester, Minnesota

Requests for reprints: Alvaro N.A. Monteiro, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-6321; Fax: 813-903-6847; E-mail: monteian{at}moffitt.usf.edu.

Germ line inactivating mutations in BRCA1 confer susceptibility for breast and ovarian cancer. However, the relevance of the many missense changes in the gene for which the effect on protein function is unknown remains unclear. Determination of which variants are causally associated with cancer is important for assessment of individual risk. We used a functional assay that measures the transactivation activity of BRCA1 in combination with analysis of protein modeling based on the structure of BRCA1 BRCT domains. In addition, the information generated was interpreted in light of genetic data. We determined the predicted cancer association of 22 BRCA1 variants and verified that the common polymorphism S1613G has no effect on BRCA1 function, even when combined with other rare variants. We estimated the specificity and sensitivity of the assay, and by meta-analysis of 47 variants, we show that variants with <45% of wild-type activity can be classified as deleterious whereas variants with >50% can be classified as neutral. In conclusion, we did functional and structure-based analyses on a large series of BRCA1 missense variants and defined a tentative threshold activity for the classification missense variants. By interpreting the validated functional data in light of additional clinical and structural evidence, we conclude that it is possible to classify all missense variants in the BRCA1 COOH-terminal region. These results bring functional assays for BRCA1 closer to clinical applicability. [Cancer Res 2007;67(4):1494–501]

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