BACKGROUND: Inactivating germline mutations in the tumour suppressor gene BRCA1 are associated with a significantly increased risk of developing breast and ovarian cancer. A large number (>1500) of unique BRCA1 variants have been identified in the population and can be classified as pathogenic, non-pathogenic or as variants of unknown significance (VUS). Many VUS are rare missense variants leading to single amino acid changes. Their impact on protein function cannot be directly inferred from sequence information, precluding assessment of their pathogenicity. Thus, functional assays are critical to assess the impact of these VUS on protein activity. BRCA1 is a multifunctional protein and different assays have been used to assess the impact of variants on different biochemical activities and biological processes. METHODS AND RESULTS: To facilitate VUS analysis, we have developed a visualisation resource that compiles and displays functional data on all documented BRCA1 missense variants. BRCA1 Circos is a web-based visualisation tool based on the freely available Circos software package. The BRCA1 Circos web tool (http://research.nhgri.nih.gov/bic/circos/) aggregates data from all published BRCA1 missense variants for functional studies, harmonises their results and presents various functionalities to search and interpret individual-level functional information for each BRCA1 missense variant. CONCLUSIONS: This research visualisation tool will serve as a quick one-stop publically available reference for all the BRCA1 missense variants that have been functionally assessed. It will facilitate meta-analysis of functional data and improve assessment of pathogenicity of VUS.

Cancer Epidemiology Program H Lee Moffitt Cancer Center and Research Institute Tampa Florida USA

Cancer Epidemiology Program H Lee Moffitt Cancer Center and Research Institute Tampa Florida USA Genome Technology Branch National Human Genome Research Institute Bethesda Maryland USA

Cancer Epidemiology Program H Lee Moffitt Cancer Center and Research Institute Tampa Florida USA University of South Florida Cancer Biology PhD Program Tampa Florida USA

Center for Cancer Research National Cancer Institute Frederick Maryland USA

CIBERER Madrid Spain

Department of Biochemistry University of Alberta Alberta Canada

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Genetics Maastricht University Medical Centre Maastricht the Netherlands

Department of Human Genetics Center for Human and Clinical Genetics Leiden University Medical Center Leiden the Netherlands

Department of Laboratory Medicine and Pathology and Health Sciences Research Mayo Clinic Rochester Minnesota USA

Department of Medical Genetics University Medical Center Utrecht Utrecht the Netherlands

Department of Population Sciences Beckman Research Institute of the City of Hope Duarte California USA

Frederick National Laboratory for Cancer Research National Cancer Institute Fredrick Maryland USA

Fundación Pública Galega de Medicina Xenómica Santiago Spain

Genetics and Population Health Division QIMR BNE Brisbane Queensland Australia

Genome Technology Branch National Human Genome Research Institute Bethesda Maryland USA

Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah USA

Institut Curie Université Pierre et Marie Curie Paris France

Instituto di Fisiologia Clinica Consiglio Nazionale delle Ricerche Pisa Italy

Instituto Federal de Educação Ciência e Tecnologia Rio de Janeiro RJ Brazil Instituto Nacional de Câncer Divisão de Farmacologia Rio de Janeiro Brazil

International Agency for Research on Cancer Lyon France

Salisbury District Hospital Salisbury Wiltshire UK

Service de Génétique Institut Curie Hôpital René Huguenin Paris France

University of Miami Medical School Miami Florida USA

University of Southampton Southampton UK

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