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Ann Oncol. 2015 Oct;26(10):2057-65. doi: 10.1093/annonc/mdv278. Epub 2015 Jul 7.

BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance.

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Faculty of Medicine Academic Unit of Cancer Sciences, Southampton General Hospital, Southampton, UK.
Familial Cancer Centre, Peter MacCallum Cancer Centre, The University of Melbourne, Melbourne, Australia Hereditary Cancer Program, Department of Medical Oncology, University of British Columbia, Vancouver, Canada.
Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, USA.
Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
Molecular Cancer Epidemiology Laboratory, Division of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, BNE, Herston, Australia.
Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands



Increasing use of BRCA1/2 testing for tailoring cancer treatment and extension of testing to tumour tissue for somatic mutation is moving BRCA1/2 mutation screening from a primarily prevention arena delivered by specialist genetic services into mainstream oncology practice. A considerable number of gene tests will identify rare variants where clinical significance cannot be inferred from sequence information alone. The proportion of variants of uncertain clinical significance (VUS) is likely to grow with lower thresholds for testing and laboratory providers with less experience of BRCA. Most VUS will not be associated with a high risk of cancer but a misinterpreted VUS has the potential to lead to mismanagement of both the patient and their relatives.


Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium ( observed wide variation in practices in reporting, disclosure and clinical management of patients with a VUS. Examples from current clinical practice are presented and discussed to illustrate potential pitfalls, explore factors contributing to misinterpretation, and propose approaches to improving clarity.


Clinicians, patients and their relatives would all benefit from an improved level of genetic literacy. Genetic laboratories working with clinical geneticists need to agree on a clinically clear and uniform format for reporting BRCA test results to non-geneticists. An international consortium of experts, collecting and integrating all available lines of evidence and classifying variants according to an internationally recognized system, will facilitate reclassification of variants for clinical use.


BRCA; VUS; classification; clinical utility; variants of uncertain significance

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