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Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics

¹ Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK
² Cancer Research UK, Human Cancer Genetics Group, Department of Oncology, University of Cambridge, UK
³ Department of Medical Genetics, Addenbrookes Hospital, Cambridge, UK
⁴ Academic Unit of Medical Genetics and Regional Genetics Service, St Mary’s Hospital, Manchester, UK
⁵ Translational Cancer Genetics Team, Institute of Cancer Research and Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, UK
⁶ Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, UK
⁷ Clinical Genetics, Guy’s Hospital, London, UK
⁸ Institute of Human Genetics, Centre for Life, Newcastle upon Tyne, UK
⁹ Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
¹⁰ Regional Medical Genetics Centre, A-Floor, Belfast HSC Trust, City Hospital Campus. Belfast, UK
¹¹ Public Health Genetics Foundation, Strangeways Research Laboratory, Cambridge, UK

Correspondence to:
Dr A C Antoniou, CR-UK Genetic Epidemiology Unit, Strangeways Reasearch Laboratory, Worts Causeway, Cambridge CB1 8RN, UK; antonis{at}srl.cam.ac.uk]

Objectives: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals.

Design: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions.

Results: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category.

Conclusions: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.