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