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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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.
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