Journal article

Splicing and Multifactorial Analysis of Intronic BRCA1 and BRCA2 Sequence Variants Identifies Clinically Significant Splicing Aberrations up to 12 Nucleotides from the Intron/Exon Boundary

Phillip J Whiley, Lucia Guidugli, Logan C Walker, Sue Healey, Bryony A Thompson, Sunil R Lakhani, Leonard M Da Silva, Sean V Tavtigian, David E Goldgar, Melissa A Brown, Fergus J Couch, Amanda B Spurdle



Clinical management of breast cancer families is complicated by identification of BRCA1 and BRCA2 sequence alterations of unknown significance. Molecular assays evaluating the effect of intronic variants on native splicing can help determine their clinical relevance. Twenty-six intronic BRCA1/2 variants ranging from the consensus dinucleotides in the splice acceptor or donor to 53 nucleotides into the intron were identified in multiple-case families. The effect of the variants on splicing was assessed using HSF matrices, MaxEntScan and NNsplice, followed by analysis of mRNA from lymphoblastoid cell lines. A total of 12 variants were associated with splicing aberrations predicted to result in..

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University of Melbourne Researchers


Awarded by National Health and Medical Research Council (NHMRC)

Awarded by NIH

Funding Acknowledgements

[ "Contract grant sponsor: The National Health and Medical Research Council (NHMRC); Contract grant number: ID442970; Contract grant sponsor: NIH; Contract grant number: CA116167; Contract grant sponsor: NIH Breast Cancer Specialized Program of research Excellence (SPORE); Contract grant number: P50 CA116201; Contract grant sponsors: National Breast Cancer Foundation (to kConFab); The NHMRC (to kConFab); The Queensland Cancer Fund (to kConFab); The Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia (to kConFab); The Cancer Foundation of Western Australia (to kConFab); NHMRC; Contract grant numbers: 145684; 288704 (to the kConFab Clinical Follow-Up Study).", "We gratefully acknowledge the participation of the families concerned. We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow-Up Study for their contributions to this resource, and the many families who contribute to kConFab. We thank Maxime Vallee for helpful discussions. We also acknowledge Linda Wadum, Kiley Johnson, Jennifer Mentlick, and Mary Karaus for their efforts to recruit the US-based families to these studies. We thank Myriad Genetic Laboratories for information used to derive family history scores and investigate co-occurrence of variants with pathogenic mutations. P.W. was awarded a scholarship by the QIMR Higher Degrees Committee. A.B.S. is an NHMRC Senior Research Fellow, L.Da.S. was supported by a fellowship from the Ludwig Institute for Cancer Research. L.W. is a John Gavin postdoctoral fellow. L.G. is supported by a fellowship from the Komen Foundation for the Cure." ]