Population frequencies of pathogenic alleles of BRCA1 and BRCA2: analysis of 173 Danish breast cancer pedigrees using the BOADICEA model
The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant in BRCA1 or BRCA2 based on her pedigree and the population frequencies of pathogenic alleles of BRCA1 (0.0006394) and BRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles of BRCA1 and BRCA2 for other populations but only includes preset values for the Ashkenazy Jewish and Icelandic populations. Among 173 early-onset breast cancer pedigrees in Denmark, BOADICEA discriminated well between carriers and non-carriers of pathogenic variants (area under the receiver operating characteristics curve: 0.81; 95% CI 0.74–0.86) but underestimated the frequency of carriers of pathogenic variants in BRCA1 or BRCA2 as measured by the observed-to-expected ratio (O/E 1.83; 95% CI 1.18–2.84). This reflects findings from older studies of BOADICEA in UK, German, Italian, and Chinese populations, all accounting for the different calibration for different carrier probabilities. To improve the performance of BOADICEA for non-UK populations, we developed a method to derive population frequencies of pathogenic alleles of BRCA1 and BRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher for BRCA1 (0.0015; 95% CI 0.00064–0.0034) and lower for BRCA2 (0.00052; 95% CI 0.00018–0.0017) after adjusting for the different calibration of BOADICEA for different carrier probabilities. Incorporating additional population frequencies into BOADICEA could improve its performance for non-UK populations.
KeywordsBreast cancer Genetic testing BRCA1 gene BRCA2 gene BOADICEA
The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm
- BWA v3
BOADICEA web application version 3
Breast cancer 1 gene
Breast cancer 2 gene
Human epidermal growth factor receptor 2
Receiver operating characteristics
Area under the ROC curve
The authors would like to thank Dr. Antonis Antoniou at the University of Cambridge, UK, for helpful comments and suggestions for the manuscript.
TT and ABS designed the study with input from the co-authors. MT and LLC interpreted the sequencing data. TT performed the statistical analyses. TT and ABS wrote the first draft. All authors revised the manuscript for intellectual content, approved the version to be published, and agree to be accountable for all aspects of the work in ensuring that questions related to the integrity of any part of the work are appropriately investigated and resolved.
The study was funded by a cancer research grant administered by Aarhus University Hospital, Denmark. The funder had no role in study design, data collection and analysis, decision to publish, or the preparation of the manuscript.
Compliance with ethical standards
Conflicts of interest
The authors declare that they had no conflicts of interest.
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