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

Setareh Moghadasi; Huong D Meeks; Maaike Pg Vreeswijk; Linda Am Janssen; Åke Borg; Hans Ehrencrona; Ylva Paulsson-Karlsson; Barbara Wappenschmidt; Christoph Engel; Andrea Gehrig; Norbert Arnold; Thomas Van Overeem Hansen; Mads Thomassen; Uffe Birk Jensen; Torben A Kruse; Bent Ejlertsen; Anne-Marie Gerdes; Inge Søkilde Pedersen; Sandrine M Caputo; Fergus Couch; Emily J Hallberg; Ans Mw van den Ouweland; Margriet J Collée; Erik Teugels; Muriel A Adank; Rob B van der Luijt; Arjen R Mensenkamp; Jan C Oosterwijk; Marinus J Blok; Nicolas Janin; Kathleen Bm Claes; Kathy Tucker; Valeria Viassolo; Amanda Ewart Toland; Diana E Eccles; Peter Devilee; Christie J Van Asperen; Amanda B Spurdle; David E Goldgar; Encarna Gómez García

doi:10.1136/jmedgenet-2017-104560

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

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

Authors

Setareh Moghadasi¹, Huong D Meeks², Maaike Pg Vreeswijk³, Linda Am Janssen¹, Åke Borg⁴, Hans Ehrencrona^{5

6}, Ylva Paulsson-Karlsson⁷, Barbara Wappenschmidt^{8

9

10}, Christoph Engel^{11

12}, Andrea Gehrig^{13

14

15}, Norbert Arnold¹⁶, Thomas Van Overeem Hansen^{17

18}, Mads Thomassen¹⁹, Uffe Birk Jensen²⁰, Torben A Kruse¹⁹, Bent Ejlertsen^{18

21}, Anne-Marie Gerdes^{18

22}, Inge Søkilde Pedersen^{23

24}, Sandrine M Caputo²⁵, Fergus Couch²⁶, Emily J Hallberg²⁷, Ans Mw van den Ouweland²⁸, Margriet J Collée²⁸, Erik Teugels²⁹, Muriel A Adank³⁰, Rob B van der Luijt^{31

32}, Arjen R Mensenkamp³³, Jan C Oosterwijk³⁴, Marinus J Blok³⁵, Nicolas Janin³⁶, Kathleen Bm Claes³⁷, Kathy Tucker³⁸, Valeria Viassolo^{39

40}, Amanda Ewart Toland⁴¹, Diana E Eccles⁴², Peter Devilee³, Christie J Van Asperen¹, Amanda B Spurdle⁴³, David E Goldgar⁴⁴, Encarna Gómez García³⁵

Affiliations

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.

PMID: 28490613
DOI: 10.1136/jmedgenet-2017-104560

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein / genetics*
Breast Neoplasms / genetics*
Chromosome Segregation
Female
Genetic Predisposition to Disease*
Humans
Mutation / genetics*
Ovarian Neoplasms / genetics*
Risk Factors

Substances

BRCA1 Protein
BRCA1 protein, human