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ORIGINAL ARTICLE |
api
2,*,
B Tice2,
R Favis3,
E Kwan1,
F Barany3,
S Manoukian4,
P Radice4,
R B van der Luijt5,
B P M van Nesselrooij5,
G Chenevix-Trench6 kConFab7,
T Caldes8,
M de La Hoya8,
S Lindquist9,
S V Tavtigian10,
D Goldgar11,
Å Borg12,
S A Narod1,
A N A Monteiro2
1 Center for Research in Women’s Health, Women’s College Hospital, Toronto, Ontario, Canada
2 Laboratory of Molecular Oncology, Strang Cancer Prevention Center, New York, USA
3 Department of Microbiology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10021, USA
4 Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy and FIRC Institute of Molecular Oncology, 20139 Milan, Italy
5 Department of Medical Genetics, University Medical Centre Utrecht, 3508 AB Utrecht, Netherlands
6 Cancer and Cell Biology Division, Queensland Institute of Medical Research, Queensland, Australia
7 Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer; Peter MacCallum Cancer Institute, East Melbourne, Australia
8 Laboratory of Molecular Oncology, Hospital Clinico San Carlos, Madrid, Spain
9 John F Kennedy Institute, Glostrup, Denmark
10 Cancer Susceptibility Unit, International Agency for Research on Cancer, Lyon, France
11 Genetic Epidemiology Unit, International Agency for Research on Cancer
12 Department of Oncology, University Hospital, Lund, Sweden
Correspondence to:
Dr Alvaro N Monteiro
H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA; monteian{at}moffitt.usf.edu]
Background: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast–ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk.
Objective: To investigate a panel of missense variants.
Methods and results: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396–1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated.
Conclusions: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.
Abbreviations: DBD, DNA binding domain
Keywords: BRCA1; mutation; transcription; tumour suppressor
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