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

Abstract

BackgroundInactivating 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 resultsTo 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.ConclusionsThis 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.

Increased centrosome number in BRCA‐related breast cancer specimens determined by immunofluorescence analysis

“…There is a debate as to whether all deleterious mutations of BRCA1/2 genes equally disrupt both functions: controlling centrosome duplication and homologous recombination . We and Cochran et al have reported that most BRCA deleterious mutations abrogate centrosome duplication and are well correlated with DNA repair function (Table ) .…”

When Genome Maintenance Goes Badly Awry

“…However, just as it has been difficult to determine the functional consequence of BRCA1/2 sequence variants identified in the germline (Jhuraney et al, 2015), it is often with uncertainty that a DNA repair defect can be ascribed to somatic missense mutations. Additionally, haploinsufficiency phenotypes have thus far not been observed in mouse models and are equivocal in highly sensitive repair assays in vitro, and importantly human tumors from carriers almost always show loss of the wild-type allele (Roy et al, 2012).…”

Trends and Developments Shaping the Future of Diagnostic Medical Imaging: 2015 Annual Oration in Diagnostic Radiology

“…Providing surveillance for disease manifestation is another role for imaging in the personalized care of patients at increased risk for cancer. For example, there are over 2000 variants of BRCA1 mutations, many of which are associated with low or moderate increased risk of cancer (42). The decision of what to do is highly personal, but enhanced surveillance with imaging may be a reasonable alternative…”