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

Journal of Medical Genetics, BMJ, ISSN 0022-2593

Volume 55, 1, 2018

DOI:10.1136/jmedgenet-2017-104560, Dimensions: pub.1085464564, PMID: 28490613,



  1. (1) Leiden University Medical Center, grid.10419.3d
  2. (2) University of Utah Health Care, grid.412722.0
  3. (3) Lund University, grid.4514.4
  4. (4) Uppsala University, grid.8993.b
  5. (5) University Hospital Cologne, grid.411097.a
  6. (6) Leipzig University, grid.9647.c
  7. (7) University of Würzburg, grid.8379.5
  8. (8) Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
  9. (9) University of Copenhagen, grid.5254.6, KU
  10. (10) Odense University Hospital, grid.7143.1, Southern Denmark Region
  11. (11) Aarhus University Hospital, grid.154185.c, Central Denmark Region
  12. (12) Aalborg Hospital, grid.27530.33, North Denmark Region
  13. (13) Institute Curie, grid.418596.7
  14. (14) Mayo Clinic, grid.66875.3a
  15. (15) Erasmus University Medical Center, grid.5645.2
  16. (16) Universitair Ziekenhuis Brussel, grid.411326.3
  17. (17) VU University Medical Center, grid.16872.3a
  18. (18) University Medical Center Utrecht, grid.7692.a
  19. (19) Radboud University Nijmegen Medical Centre, grid.10417.33
  20. (20) Department of Genetics, University of Groningen, University Medical Centre, Groningen, The Netherlands.
  21. (21) Maastricht University Medical Centre, grid.412966.e
  22. (22) Cliniques Universitaires Saint-Luc, grid.48769.34
  23. (23) Ghent University Hospital, grid.410566.0
  24. (24) Hereditary Cancer Service, Prince of Wales (and St George Hospitals) Hospital, Randwick, New South Wales, Australia.
  25. (25) University Hospital of Geneva, grid.150338.c
  26. (26) The Ohio State University, grid.261331.4
  27. (27) University of Southampton, grid.5491.9
  28. (28) QIMR Berghofer Medical Research Institute, grid.1049.c
  29. (29) University of Utah, grid.223827.e


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.


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