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Human Molecular Genetics, 2001, Vol. 10, No. 4 353-360
© 2001 Oxford University Press

Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families

Johan Vallon-Christersson1, Charmagne Cayanan7, Karin Haraldsson1, Niklas Loman1, Jon Thor Bergthorsson3, Karen Brøndum-Nielsen4, Anne-Marie Gerdes5, Pål Møller6, Ulf Kristoffersson2, Håkan Olsson1, Åke Borg1 and Alvaro N.A. Monteiro7,8,+

1Department of Oncology and 2Department of Clinical Genetics, University Hospital, SE-221 85 Lund, Sweden, 3Department of Pathology, University Hospital of Iceland, IS-121 Reykjavik, Iceland, 4The John F. Kennedy Institute, 2600 Glostrup, Denmark, 5Department of Clinical Genetics, University Hospital, 2100 Copenhagen, Denmark, 6Unit of Medical Genetics, the Norwegian Radium Hospital, N-0310 Oslo, Norway, 7Laboratory of Molecular Oncology, Strang Cancer Prevention Center, New York, NY 10021, USA and 8Department of Cell Biology, Weill Medical College of Cornell University, New York, NY 10021, USA

Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1 are responsible for the majority of cases involving hereditary breast and ovarian cancer. Whereas all truncating mutations are considered as functionally deleterious, most of the missense variants identified to date cannot be readily distinguished as either disease-associated mutations or benign polymorphisms. The C-terminal domain of BRCA1 displays an intrinsic transactivation activity, and mutations linked to disease predisposition have been shown to confer loss of such activity in yeast and mammalian cells. In an attempt to clarify the functional importance of the BRCA1 C-terminus as a transcription activator in cancer predisposition, we have characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Missense variants A1669S, C1697R, R1699W, R1699Q, A1708E, S1715R and G1738E and a truncating mutation, W1837X, were characterized using yeast- and mammalian-based transcription assays. In addition, four additional missense variants (V1665M, D1692N, S1715N and D1733G) and one in-frame deletion (V1688del) were included in the study. Our findings demonstrate that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. We also report a discrepancy between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. We show that transcription-based assays can aid in the characterization of deleterious mutations in the C-terminal part of BRCA1 and may form the basis of a functional assay.

+ To whom correspondence should be addressed at: Laboratory of Molecular Oncology, Strang Cancer Prevention Center, The Rockefeller University, Box 231, 1230 York Avenue, New York, NY 10021, USA. Tel: +1 212 7340567 (ext. 225); Fax: +1 212 4729471; Email: monteia@rockvax.rockefeller.edu


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