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Short Report
The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
  1. Setareh Moghadasi1,
  2. Huong D Meeks2,
  3. Maaike PG Vreeswijk3,
  4. Linda AM Janssen1,
  5. Åke Borg4,
  6. Hans Ehrencrona5,6,
  7. Ylva Paulsson-Karlsson7,
  8. Barbara Wappenschmidt8,9,10,
  9. Christoph Engel11,12,
  10. Andrea Gehrig13,14,15,
  11. Norbert Arnold16,
  12. Thomas Van Overeem Hansen17,18,
  13. Mads Thomassen19,
  14. Uffe Birk Jensen20,
  15. Torben A Kruse19,
  16. Bent Ejlertsen18,21,
  17. Anne-Marie Gerdes18,22,
  18. Inge Søkilde Pedersen23,24,
  19. Sandrine M Caputo25,
  20. Fergus Couch26,
  21. Emily J Hallberg27,
  22. Ans MW van den Ouweland28,
  23. Margriet J Collée28,
  24. Erik Teugels29,
  25. Muriel A Adank30,
  26. Rob B van der Luijt31,32,
  27. Arjen R Mensenkamp33,
  28. Jan C Oosterwijk34,
  29. Marinus J Blok35,
  30. Nicolas Janin36,
  31. Kathleen BM Claes37,
  32. Kathy Tucker38,
  33. Valeria Viassolo39,40,
  34. Amanda Ewart Toland41,
  35. Diana E Eccles42,
  36. Peter Devilee3,
  37. Christie J Van Asperen1,
  38. Amanda B Spurdle43,
  39. David E Goldgar44,
  40. Encarna Gómez García35
  1. 1 Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  2. 2 Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
  3. 3 Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
  4. 4 Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
  5. 5 Department of Clinical Genetics, Lund University, Lund, Sweden
  6. 6 Department of Clinical Genetics, Laboratory Medicine, Office for Medical Services, Lund University, Lund, Sweden
  7. 7 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  8. 8 Centre of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
  9. 9 Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany
  10. 10 Centre for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany
  11. 11 Institute for Medical Informatics, University of Leipzig, Leipzig, Germany
  12. 12 Department of Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  13. 13 Centre of Familial Breast and Ovarian Cancer, University Würzburg, Würzburg, Germany
  14. 14 Department of Medical Genetics, University Würzburg, Würzburg, Germany
  15. 15 Institute of Human Genetics, University Würzburg, Würzburg, Germany
  16. 16 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  17. 17 Center for Genomic Medicine, University of Copenhagen, Copenhagen, DenmarK
  18. 18 Department of Rigshospitalet, University of Copenhagen, Copenhagen, DenmarK
  19. 19 Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
  20. 20 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  21. 21 Department of Oncology, University of Copenhagen, Copenhagen, Denmark
  22. 22 Department of Clinical Genetics, University of Copenhagen, Copenhagen, Denmark
  23. 23 Section of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
  24. 24 Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
  25. 25 Institut Curie, Service de génétique, Paris, France
  26. 26 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
  27. 27 Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  28. 28 Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
  29. 29 Familial Cancer Clinic and Medical Oncology, University Hospital Brussels, Belgium
  30. 30 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
  31. 31 Division of Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  32. 32 Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  33. 33 Department of Human Genetics, Radboudumc Nijmegen, The Netherlands
  34. 34 Department of Genetics, University of Groningen, University Medical Centre, Groningen, The Netherlands
  35. 35 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
  36. 36 Department of Service de Génétique, Cliniques universitaires Saint-Luc, Bruxelles, Belgium
  37. 37 Centre for Medical Genetics, Ghent University Hospital, Belgium
  38. 38 Hereditary Cancer Service, Prince of Wales (and St George Hospitals) Hospital, Randwick, New South Wales, Australia
  39. 39 Department of Oncogenetics and Cancer Prevention Unit, Geneva University Hospitals, Geneva, Switzerland
  40. 40 Division of Oncology, Geneva University Hospitals, Geneva, Switzerland
  41. 41 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
  42. 42 Faculty of Medicine, University of Southampton, Southampton, UK
  43. 43 Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia
  44. 44 Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine Salt Lake City, Salt Lake City, Utah, USA
  1. Correspondence to Dr Encarna Gómez García, Department of Clinical Genetics Maastricht University Medical Centre, Maastricht 6202 AZ, The Netherlands; encarna.gomezgarcia{at}


Background We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers.

Methods Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.

Results In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).

Conclusion Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

  • BRCA1
  • R1699Q
  • breastcancer
  • ovarian cancer
  • intermediate cancer risk
  • Surveillance

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  • SM and HDM contributed equally.

  • Funding The Netherlands Organization for Scientific Research (NWO), research program Mosaic (Grant 017.008.022); Van de Kampfonds from Leiden University Medical Centre (Grant 30.925). ABS is supported by an Australian NHMRC Senior Research Fellowship. SMC was supported by the French National Cancer Institute (INCa).

  • Competing interests EGG has received an honorarium in the past 3 years from AstraZeneca for giving a course and a lecture. HE (or rather, his department with him as primary contact) has received funding from Novartis Oncology (unrestricted grant) and AstraZeneca (invited speaker). KT has received an honorarium for chairing a mainstreaming genetic testing subcommittee and day seminar for AstraZeneca. AET declares to have received an honorarium from American Cancer Society for grant review, NIH NCI PDQ as editorial board, Italian Ministry of Health for grant review. DEE receives an honorarium from AstraZeneca via a contract with the university to provide consultancy advice from time to time (one or two advisory boards each year on average at the moment). DEG has received royalties from patents on the BRCA1 and BRCA2 genes from the University of Utah that are licensed to Myriad Genetics. All the other authors declare to have no conflicts of interest.

  • Ethics approval All authors made a significant contribution to data collection, data interpretation, writing and critical assessment of this study.

    Specifically: SM, EGG, DEG and ABS were responsible for study concept and design. HDM and DEG performed the statistical analyses. SM and EGG wrote the manuscript.

    SM, EGG, LAMJ and MPGV were responsible for data collection. K

    BMC, HE, YPK, BW, CE, AG, NA, TvOH, MT, UBJ, TAK, BE, AMG, ISP, SMC, FC, EJH, AMWvdO, MJC, ET, MAA, RBvdL, ARM, JCO, MJB, NJ, KC, KT, VV, AET, DEE, PD and CJvA provided the family data analysed in this study.

    EGG coordinated the study.

    All authors approved the final manuscript submitted.

  • Ethics approval Not applicable.

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