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Familial Cancer

, Volume 18, Issue 4, pp 381–388 | Cite as

Population frequencies of pathogenic alleles of BRCA1 and BRCA2: analysis of 173 Danish breast cancer pedigrees using the BOADICEA model

  • Thorkild TerkelsenEmail author
  • Lise-Lotte Christensen
  • Deirdre Cronin Fenton
  • Uffe Birk Jensen
  • Lone Sunde
  • Mads Thomassen
  • Anne-Bine Skytte
Original Article

Abstract

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.

Keywords

Breast cancer Genetic testing BRCA1 gene BRCA2 gene BOADICEA 

Abbreviations

BOADICEA

The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm

BWA v3

BOADICEA web application version 3

BRCA1

Breast cancer 1 gene

BRCA2

Breast cancer 2 gene

ER

Estrogen receptor

HER2

Human epidermal growth factor receptor 2

ROC

Receiver operating characteristics

AUC

Area under the ROC curve

O/E

Observed-to-expected ratio

UK

United Kingdom

Notes

Acknowledgements

The authors would like to thank Dr. Antonis Antoniou at the University of Cambridge, UK, for helpful comments and suggestions for the manuscript.

Author contributions

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.

Funding

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.

Supplementary material

10689_2019_141_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 57 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Clinical GeneticsAarhus University HospitalAarhus NDenmark
  2. 2.Department of Molecular MedicineAarhus University HospitalAarhusDenmark
  3. 3.Department of Clinical EpidemiologyAarhus University HospitalAarhusDenmark
  4. 4.Department of Clinical GeneticsOdense University HospitalOdenseDenmark

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