Abstract
Background:Thousands of clinically relevant variations in BRCA1 and BRCA2 have been discovered and this poses a significant challenge with respect to the accurate detection, analysis turn-around time, characterisation and interpretation of these sequence variants.Methods:We evaluated the performance of different BRCA1/2 gene testing practices in routine diagnostic use in 20 European laboratories, with a focus on next-generation sequencing-based strategies as this is the technical approach implemented by or under adoption by most European clinical laboratories. Participant laboratories, selected on expertise and diagnostic service quality, tested 10 identical DNA samples containing a range of challenging pathogenic variants.Results:A small number of errors in the detection of pathogenic and significant variants were identified (2.6% diagnostic error rate). There was a high degree of concordance (>97%) across all laboratories for all variants detected. No systematic technical flaw was identified in the strategies employed across the participating laboratories.Conclusions:The discrepancies identified are most likely due to human error or the way the methodology has been implemented locally, for example, next-generation sequencing bioinformatics pipelines, rather than technical limitations of the methods. The choice of BRCA1/2 testing method will therefore depend on multiple factors including required throughput and turn-around times, access to equipment, expertise and budget.
Highlights
MethodsWe evaluated the performance of different BRCA1/2 gene testing practices in routine diagnostic use in 20 European laboratories, with a focus on next-generation sequencing-based strategies as this is the technical approach implemented by or under adoption by most European clinical laboratories
Thousands of clinically relevant variations in BRCA1 and BRCA2 have been discovered and this poses a significant challenge with respect to the accurate detection, analysis turn-around time, characterisation and interpretation of these sequence variants
The choice of BRCA1/2 testing method will depend on multiple factors including required throughput and turn-around times, access to equipment, expertise and budget
Summary
We evaluated the performance of different BRCA1/2 gene testing practices in routine diagnostic use in 20 European laboratories, with a focus on next-generation sequencing-based strategies as this is the technical approach implemented by or under adoption by most European clinical laboratories. In Part A of the study a short survey of current BRCA1/2 gene screening methods was circulated to 156 members of the EMQN network participating in the 2014 EQA scheme for BRCA testing. The survey was used to establish the current state-of-the-art in BRCA testing among the EMQN member laboratories and to inform laboratory selection for Part B of the study. Participation by selected laboratories was voluntary – all agreed to take part These laboratories had demonstrated a significant diagnostic BRCA testing caseload per annum (4300 germline BRCA1/2 mutation analyses), conducted all testing in their own laboratory (no outsourcing or subcontracting of their testing process) and had demonstrated evidence of successful participation in three successive years in a recognised External Quality Assurance (EQA) scheme (e.g., EMQN, UK National External Quality Assessment Scheme (UK NEQAS) for Molecular Genetics, or College of American Pathology (CAP)). We selected laboratories which were accredited to the ISO15189 medical laboratory standard as this gave additional assurances and confidence that the lab was performing high-quality testing
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