BRCA1 Circos: a visualisation resource for functional analysis of missense variants

Ankita Jhuraney, Aneliya Velkova, Randall C. Johnson, Bailey Kessing, Renato S. Carvalho, Phillip Whiley, Amanda B. Spurdle, Maaike P. G. Vreeswijk, Sandrine M. Caputo, Gael A. Millot, Ana Vega, Nicolas Coquelle, Alvaro Galli, Diana Eccles, Marinus J. Blok, Tuya Pal, Rob B. van der Luijt, Marta Santamarina Pena, Susan L. Neuhausen, Talia DonenbergEva Machackova, Simon Thomas, Maxime Vallee, Fergus J. Couch, Sean V. Tavtigian, J. N. Mark Glover, Marcelo A. Carvalho, Lawrence C. Brody, Shyam K. Sharan, Alvaro N. Monteiro*, ENIGMA Evidence-Based Network

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)224-230
Number of pages7
JournalJOURNAL OF MEDICAL GENETICS
Volume52
Issue number4
DOIs
Publication statusPublished - Apr-2015

Keywords

  • UNKNOWN CLINICAL-SIGNIFICANCE
  • BREAST-CANCER RISK
  • MUTATION-POSITIVE FAMILIES
  • OVARIAN-CANCER
  • UNCERTAIN SIGNIFICANCE
  • SEQUENCE VARIANTS
  • GENETIC-ANALYSIS
  • LIGASE ACTIVITY
  • NEGATIVE WOMEN
  • RING-DOMAIN

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