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

AbstractThe Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) calculates the probability that a woman carries a pathogenic variant inBRCA1 orBRCA2 based on her pedigree and the population frequencies of pathogenic alleles ofBRCA1 (0.0006394) andBRCA2 (0.00102) in the United Kingdom (UK). BOADICEA allows the clinician to define the population frequencies of pathogenic alleles ofBRCA1 andBRCA2 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 inBRCA1 orBRCA2 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 ofBRCA1 andBRCA2. Compared to the UK population frequencies, we estimated the Danish population frequencies of pathogenic alleles to be higher forBRCA1 (0.0015; 95% CI 0.00064 –0.0034) and lower forBRCA2 (0.00052; 95% CI 0.00018 –0.0017...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research