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Classification of BRCA1 missense variants of unknown clinical significance
  1. C M Phelan1,*,
  2. V Đapić2,*,
  3. B Tice2,
  4. R Favis3,
  5. E Kwan1,
  6. F Barany3,
  7. S Manoukian4,
  8. P Radice4,
  9. R B van der Luijt5,
  10. B P M van Nesselrooij5,
  11. G Chenevix-Trench6,
  12. kConFab7,
  13. T Caldes8,
  14. M de La Hoya8,
  15. S Lindquist9,
  16. S V Tavtigian10,
  17. D Goldgar11,
  18. Å Borg12,
  19. S A Narod1,
  20. A N A Monteiro2
  1. 1Center for Research in Women’s Health, Women’s College Hospital, Toronto, Ontario, Canada
  2. 2Laboratory of Molecular Oncology, Strang Cancer Prevention Center, New York, USA
  3. 3Department of Microbiology, Joan and Sanford I. Weill Medical College of Cornell University, New York, NY 10021, USA
  4. 4Department of Experimental Oncology, Istituto Nazionale Tumori, 20133 Milan, Italy and FIRC Institute of Molecular Oncology, 20139 Milan, Italy
  5. 5Department of Medical Genetics, University Medical Centre Utrecht, 3508 AB Utrecht, Netherlands
  6. 6Cancer and Cell Biology Division, Queensland Institute of Medical Research, Queensland, Australia
  7. 7Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer; Peter MacCallum Cancer Institute, East Melbourne, Australia
  8. 8Laboratory of Molecular Oncology, Hospital Clinico San Carlos, Madrid, Spain
  9. 9John F Kennedy Institute, Glostrup, Denmark
  10. 10Cancer Susceptibility Unit, International Agency for Research on Cancer, Lyon, France
  11. 11Genetic Epidemiology Unit, International Agency for Research on Cancer
  12. 12Department of Oncology, University Hospital, Lund, Sweden
  1. Correspondence to:
 Dr Alvaro N Monteiro
 H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA;


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.

  • DBD, DNA binding domain
  • BRCA1
  • mutation
  • transcription
  • tumour suppressor

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  • * These authors contributed equally to this work

  • Conflicts of interest: none declared