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Variant effect on splicing regulatory elements, branchpoint usage, and pseudoexonization: strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars
  • Daffodil Canson,
  • Dylan Glubb,
  • Amanda Spurdle
Daffodil Canson
QIMR Berghofer Medical Research Institute
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Dylan Glubb
QIMR Berghofer Medical Research Institute
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Amanda Spurdle
QIMR Berghofer Medical Research Institute
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It is possible to estimate the prior probability of pathogenicity for germline disease gene variants based on bioinformatic prediction of variant effect/s. However, routinely used approaches have likely led to the underestimation and underreporting of variants located outside donor and acceptor splice site motifs that affect mRNA processing. This review presents information about hereditary cancer gene germline variants, outside native splice sites, with experimentally validated splicing effects. We list 81 exonic variants that impact splicing regulatory elements in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2. We utilized a pre-existing large-scale BRCA1 functional dataset to map functional splicing regulatory elements, assess the relative performance of different tools to predict effects of 283 variants on such elements, and develop a generic workflow to prioritize variants that may impact splicing regulatory elements. We also describe rare examples of intronic variants that impact branchpoint sites and create pseudoexons. We discuss the challenges in predicting variant effect on branchpoint site usage and pseudoexonization, and suggest strategies to improve the bioinformatic prioritization of such variants for experimental validation. Importantly, our review highlights the importance of considering impact of variants outside donor and acceptor motifs on mRNA splicing and disease causation.

Peer review status:ACCEPTED

06 Mar 2020Submitted to Human Mutation
10 Mar 2020Submission Checks Completed
10 Mar 2020Assigned to Editor
17 Mar 2020Reviewer(s) Assigned
21 Apr 2020Review(s) Completed, Editorial Evaluation Pending
26 Apr 2020Editorial Decision: Revise Minor
24 Jun 20201st Revision Received
27 Jun 2020Submission Checks Completed
27 Jun 2020Assigned to Editor
29 Jun 2020Review(s) Completed, Editorial Evaluation Pending
02 Jul 2020Editorial Decision: Accept