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BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk
  1. Amanda B Spurdle1,2,
  2. Phillip J Whiley1,
  3. Bryony Thompson1,2,
  4. Bingjian Feng3,
  5. Sue Healey1,
  6. Melissa A Brown4,
  7. Christopher Pettigrew4,
  8. kConFab5,
  9. Christi J Van Asperen6,
  10. Margreet G E M Ausems7,
  11. Anna A Kattentidt-Mouravieva8,
  12. Ans M W van den Ouweland8,
  13. Dutch Belgium UV Consortium9,10,
  14. Annika Lindblom11,
  15. Maritta H Pigg12,
  16. Rita K Schmutzler13,
  17. Christoph Engel14,
  18. Alfons Meindl15,
  19. German Consortium of Hereditary Breast and Ovarian Cancer9,13,
  20. Sandrine Caputo16,
  21. Olga M Sinilnikova17,18,
  22. Rosette Lidereau16,
  23. French COVAR group collaborators19,
  24. Fergus J Couch20,
  25. Lucia Guidugli20,
  26. Thomas van Overeem Hansen21,
  27. Mads Thomassen22,
  28. Diana M Eccles23,
  29. Kathy Tucker24,
  30. Javier Benitez25,
  31. Susan M Domchek26,
  32. Amanda E Toland27,
  33. Elizabeth J Van Rensburg28,
  34. Barbara Wappenschmidt13,
  35. Åke Borg29,
  36. Maaike P G Vreeswijk30,
  37. David E Goldgar3,31 on behalf of the ENIGMA Consortium9
  1. 1Division of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  2. 2School of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. 3Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah, USA
  4. 4School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia
  5. 5Peter MacCallum Cancer Institute, Melbourne, Victoria 3000, Australia
  6. 6Department of Clinical Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  7. 7Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  8. 8Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
  9. 9See Appendix for full list of ENIGMA collaborators contributing to this study, operating within and outside of country consortia
  10. 10Dutch Belgium UV Consortium, Co-ordinator F.B. Hogervorst, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  11. 11Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  12. 12Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
  13. 13Department of Gynaecology and Obstetrics, Centre of Familial Breast and Ovarian Cancer and Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
  14. 14Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  15. 15Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany
  16. 16Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM, Saint-Cloud, France
  17. 17Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon/Centre Leon Berard, Lyon, France
  18. 18INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France
  19. 19French COVAR group collaborators co-ordinator Rosette Lidereau, Institut Curie, Hôpital René Huguenin, Service d'Oncogénétique, U735 INSERM—Saint-Cloud, France
  20. 20Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  21. 21Center for Genomic Medicine, Rigshospitalet, Copenhagen University hospital, Copenhagen, Denmark
  22. 22Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
  23. 23Faculty of Medicine, University of Southampton, Southampton University Hospital NHS Trust MP824, Southampton, UK
  24. 24Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick, Australia
  25. 25Spanish National Cancer Centre, Madrid, Spain
  26. 26Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  27. 27Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, OSU Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
  28. 28Department of Genetics, University of Pretoria, Hatfield, South Africa
  29. 29Åke Borg, Department of Oncology, Lund University, Lund, Sweden
  30. 30Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  31. 31Huntsman Cancer Institute, Salt Lake City, Utah, USA
  1. Correspondence to Dr Amanda B Spurdle, Division of Genetics and Population Health, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia; Amanda.Spurdle{at}; Professor David E Goldgar, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA; david.goldgar{at}


Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p.Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer.

Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X).

Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘BRCA1-like’ than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p.Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%.

Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

  • Cancer: breast
  • Genetics
  • Genetic epidemiology

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  • Additional supplementary figures are published online only. To view these files please visit the journal online (

  • Funding This work was supported in part by project grants from The National Health and Medical Research Council (NHMRC) to ABS. ABS is supported by an NHMRC Senior Research Fellowship. kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by NHMRC grants (145684 and 288704). BJF is supported by the Canadian Institutes of Health Research Team Grant in Familial Risks of Breast Cancer CRN-87521. AL thanks the Swedish Cancer Society for support. The work of the German Consortium GC-HBOC is supported by a grant of the German Cancer Aid (grant 107364, RKS) and by the Centre for Molecular Medicine Cologne, Cologne, Germany (RKS, BW). The French Consortium thanks the Association d'Aide à la Recherche Cancérologique de Saint Cloud (ARCs) and the Ligue 92 contre le Cancer for their financial support. FJC and DEG are supported by NIH grant CA116167, an NIH Recovery Act supplement (CA116167Z), and an NIH Specialised Programme of Research Excellence (SPORE) in Breast Cancer (CA116201). LG is supported by a Komen Race for the Cure Fellowship. Research by TvOH was supported by the NEYE Foundation. SMD is supported by funding from the Komen Foundation for the Cure. Ohio State University CCG is supported by the OSU Comprehensive Cancer Center (AET). EJVR is funded by grants from the Cancer Association of South Africa. The research coordinated by MPGV was supported by Dutch Cancer Society grants 2001-2471 and 2006-3677. DEG is supported by NIH grant CA116167. Coordination of ENIGMA is funded by The National Institutes of Health Recovery Act supplement award (CA116167Z).

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.