Abstract
The advent of high-throughput sequencing has accelerated our ability to discover genes predisposing to disease and is transforming clinical genomic sequencing. In both contexts knowledge of the spectrum and frequency of genetic variation in the general population and in disease cohorts is vital to the interpretation of sequencing data. While population level data is becoming increasingly available from publicly accessible sources, as exemplified by The Exome Aggregation Consortium (ExAC), the availability of large-scale disease-specific frequency information is limited. These data are of particular importance to contextualise findings from clinical mutation screens and small gene discovery projects. This is especially true for cancer, which is typified by a number of hereditary predisposition syndromes. Although mutation frequencies in tumours are available from resources such as Cosmic and The Cancer Genome Atlas, a similar facility for germline variation is lacking. Here we present the Cancer Variation Resource (CanVar) an online database which has been developed using the ExAC framework to provide open access to germline variant frequency data from the sequenced exomes of cancer patients. In its first release, CanVar catalogues the exomes of 1,006 familial early-onset colorectal cancer (CRC) patients sequenced at The Institute of Cancer Research. It is anticipated that CanVar will host data for additional cancers, providing a resource for others studying cancer predisposition and an example of how the research community can utilise the ExAC framework to share sequencing data.
Highlights
With the widespread adoption of high-throughput sequencing as a tool for disease gene discovery and clinical diagnostics there is a need to evaluate candidate disease predisposition genes through defining the spectrum and frequency of genetic variation in the general population and in specific disease cohorts
We present an adaptation of the Exome Aggregation Consortium (ExAC) framework to create Cancer Variation Resource (CanVar), a cancer specific online resource for germline sequencing data
The data currently catalogued in CanVar will provide a valuable resource for researchers investigating genetic predisposition to colorectal cancer and those engaged in delivery of clinical cancer genetic testing programs
Summary
With the widespread adoption of high-throughput sequencing as a tool for disease gene discovery and clinical diagnostics there is a need to evaluate candidate disease predisposition genes through defining the spectrum and frequency of genetic variation in the general population and in specific disease cohorts. For this to be meaningful, large sample sizes are required in order that variant frequencies are accurately defined. When undertaken by multiple agencies, this results in considerable duplication of effort, the products of which may not be widely shared It is desirable for large, processed sequencing datasets to be made accessible to the community. The ExAC website presents these data as variant frequencies stratified by different ethnic groups alongside additional sequencing quality metrics and transcript based annotations
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