An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice

Gillian Ellison, Miika Ahdesmäki, Sally Luke, Paul M Waring, Andrew Wallace, Ronnie Wright, Benno Röthlisberger, Katja Ludin, Sabine Merkelbach-Bruse, Carina Heydt, Marjolijn J L Ligtenberg, Arjen R Mensenkamp, David Gonzalez de Castro, Thomas Jones, Ana Vivancos, Olga Kondrashova, Patrick Pauwels, Christine Weyn, Eric Hahnen, Jan HaukeRichie Soong, Zhongwu Lai, Brian Dougherty, T Hedley Carr, Justin Johnson, John Mills, J Carl Barrett

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
164 Downloads (Pure)


Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

Original languageEnglish
Number of pages12
JournalHuman Mutation
Early online date28 Dec 2017
Publication statusEarly online date - 28 Dec 2017


  • Journal Article


Dive into the research topics of 'An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice'. Together they form a unique fingerprint.

Cite this