title: BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Members of the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) global consortium (www.enigmaconsortium.org) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Medicine Academic Unit of Cancer Sciences, Southampton General Hospital, Southampton, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Eccles
authors.affiliation: 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.
authors.forename: G
authors.initials: G
authors.lastname: Mitchell
authors.affiliation: Cancer Epidemiology Program, H. Lee Moffitt Cancer Center, Tampa, USA.
authors.forename: A N A
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Cologne, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Schmutzler
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA.
authors.forename: F J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Molecular Cancer Epidemiology Laboratory, Division of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, BNE, Herston, Australia.
authors.forename: A B
authors.initials: AB
authors.lastname: Spurdle
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands Encarna.Gomezgarcia@mumc.nl.
authors.forename: E B
authors.initials: EB
authors.lastname: Gómez-García
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics; D003627:Data Interpretation, Statistical; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000592:standards*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics; D017410:Practice Guidelines as Topic; D011379:Prognosis; D012307:Risk Factors
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA; VUS; classification; clinical utility; variants of uncertain significance