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J Med Genet. 2018 Jan;55(1):15-20. doi: 10.1136/jmedgenet-2017-104560. Epub 2017 May 10.

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.

Author information

1
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
2
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
3
Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
4
Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden.
5
Department of Clinical Genetics, Lund University, Lund, Sweden.
6
Department of Clinical Genetics, Laboratory Medicine, Office for Medical Services, Lund University, Lund, Sweden.
7
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
8
Centre of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
9
Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
10
Centre for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany.
11
Institute for Medical Informatics, University of Leipzig, Leipzig, Germany.
12
Department of Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
13
Centre of Familial Breast and Ovarian Cancer, University Würzburg, Würzburg, Germany.
14
Department of Medical Genetics, University Würzburg, Würzburg, Germany.
15
Institute of Human Genetics, University Würzburg, Würzburg, Germany.
16
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
17
Center for Genomic Medicine, University of Copenhagen, Copenhagen, DenmarK.
18
Department of Rigshospitalet, University of Copenhagen, Copenhagen, DenmarK.
19
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
20
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
21
Department of Oncology, University of Copenhagen, Copenhagen, Denmark.
22
Department of Clinical Genetics, University of Copenhagen, Copenhagen, Denmark.
23
Section of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
24
Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
25
Institut Curie, Service de génétique, Paris, France.
26
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
27
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
28
Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
29
Familial Cancer Clinic and Medical Oncology, University Hospital Brussels, Belgium.
30
Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands.
31
Division of Biomedical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
32
Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
33
Department of Human Genetics, Radboudumc Nijmegen, The Netherlands.
34
Department of Genetics, University of Groningen, University Medical Centre, Groningen, The Netherlands.
35
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
36
Department of Service de Génétique, Cliniques universitaires Saint-Luc, Bruxelles, Belgium.
37
Centre for Medical Genetics, Ghent University Hospital, Belgium.
38
Hereditary Cancer Service, Prince of Wales (and St George Hospitals) Hospital, Randwick, New South Wales, Australia.
39
Department of Oncogenetics and Cancer Prevention Unit, Geneva University Hospitals, Geneva, Switzerland.
40
Division of Oncology, Geneva University Hospitals, Geneva, Switzerland.
41
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA.
42
Faculty of Medicine, University of Southampton, Southampton, UK.
43
Genetics and Computational Biology Division, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia.
44
Huntsman Cancer Institute and Department of Dermatology, University of Utah School of Medicine Salt Lake City, Salt Lake City, Utah, USA.

Abstract

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.

KEYWORDS:

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

PMID:
28490613
DOI:
10.1136/jmedgenet-2017-104560
[Indexed for MEDLINE]

Conflict of interest statement

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.

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