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The contribution of germline rearrangements to the spectrum of BRCA2 mutations
  1. F Casilli1,
  2. I Tournier1,
  3. O M Sinilnikova2,
  4. F Coulet3,
  5. F Soubrier3,
  6. C Houdayer4,
  7. A Hardouin5,
  8. P Berthet5,
  9. H Sobol6,
  10. V Bourdon6,
  11. D Muller7,
  12. J P Fricker7,
  13. C Capoulade-Metay8,
  14. A Chompret8,
  15. C Nogues9,
  16. S Mazoyer10,
  17. P Chappuis11,
  18. P Maillet11,
  19. C Philippe12,
  20. A Lortholary13,
  21. P Gesta14,
  22. S Bézieau15,
  23. C Toulas16,
  24. L Gladieff16,
  25. C M Maugard17,
  26. D M Provencher17,
  27. C Dugast18,
  28. C Delvincourt19,
  29. T D Nguyen19,
  30. L Faivre20,
  31. V Bonadona21,
  32. T Frébourg1,
  33. R Lidereau9,
  34. D Stoppa-Lyonnet4,
  35. M Tosi1
  1. 1Inserm U614, IFRMP, Faculty of Medicine, Rouen, France
  2. 2Plate-forme Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France
  3. 3Unité d’Oncogénétique et Angiogénétique Moléculaire, Pitié Salpétrière, Paris, France
  4. 4Service de Génétique Oncologique, Institut Curie, Paris, France
  5. 5Laboratoire de Biologie Clinique et Oncologique, Centre François Baclesse, Caen, France
  6. 6Inserm EPI 9939, Institut Paoli-Calmettes, Marseille, France
  7. 7Unité d’Oncogénétique, Centre de Lutte Contre le Cancer Paul Strauss, Strasbourg, France
  8. 8Service de Génétique, Institut Gustave Roussy, Villejuif, France
  9. 9Service d’Oncogénétique, Inserm U735, Centre René Huguenin, Saint-Cloud, France
  10. 10Laboratoire de Génétique, UMR5201 CNRS, Université Claude Bernard Lyon I, Lyon, France
  11. 11Service d’Oncologie, Hôpital Universitaire de Genève, Geneva, Switzerland
  12. 12Laboratoire de Génétique, CHU, Nancy, France
  13. 13Centre Catherine de Sienne, Nantes, France
  14. 14Service d’Oncologie, Centre Hospitalier, Niort, France
  15. 15Laboratoire de Génétique Moléculaire, CHU, Nantes, France
  16. 16Institut Claudius Regaud, Toulouse, France
  17. 17CR-CHUM, Service de Médecine Génique, Département de Médecine, Université de Montréal, Montreal, Canada
  18. 18Centre Régional de Lutte Contre le Cancer Eugene Marquis, Rennes, France
  19. 19Centre Régional de Lutte Contre le Cancer Institut Jean Godinot, Reims, France
  20. 20Oncogénétique, Centre Georges Francois Leclerc et Hôpital Le Bocage, Dijon, France
  21. 21Unité de Prévention et d’Epidémiologie Génétique, Centre Léon Bérard, Lyon, France
  1. Correspondence to:
 Mario Tosi
 Inserm U614, Faculty of Medicine, 22 boulevard Gambetta, 76183 Rouen, France; mario.tosi{at}


Background: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer.

Objective: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects.

Methods: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2.

Results: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of ⩽50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum.

Conclusion: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

  • familial breast cancer
  • molecular diagnosis
  • quantitative multiplex PCR of short fluorescent fragments

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  • This work has been supported by grants from Association pour la Recherche sur le Cancer (ARC) and Ligue contre le Cancer, Comité de l’Eure. I Tournier was supported by a fellowship from Ministère de l’Education Nationale, de la Recherche et de la Technologie (MENRT) and is currently supported by a fellowship from ARC.

  • Competing interests: none declared