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

Whiley, Phillip J., Guidugli, Lucia, Walker, Logan C., Healey, Sue, Thompson, Bryony A., Lakhani, Sunil R., Da Silva, Leonard M., kConFab Investigators, Tavtigian, Sean V., Goldgar, David E., Brown, Melissa A., Couch, Fergus J. and Spurdle, Amanda B. (2011) 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. Human Mutation, 32 6: 678-687. doi:10.1002/humu.21495

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Author Whiley, Phillip J.
Guidugli, Lucia
Walker, Logan C.
Healey, Sue
Thompson, Bryony A.
Lakhani, Sunil R.
Da Silva, Leonard M.
kConFab Investigators
Tavtigian, Sean V.
Goldgar, David E.
Brown, Melissa A.
Couch, Fergus J.
Spurdle, Amanda B.
Title 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
Formatted title
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
Journal name Human Mutation   Check publisher's open access policy
ISSN 1059-7794
1098-1004
Publication date 2011-06
Sub-type Article (original research)
DOI 10.1002/humu.21495
Volume 32
Issue 6
Start page 678
End page 687
Total pages 10
Place of publication Hoboken, NJ, U.S.A.
Publisher John Wiley & Sons
Collection year 2012
Language eng
Formatted abstract
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 production of truncated proteins, including a variant located 12 nucleotides into the intron. The posterior probability of pathogenicity was estimated using a multifactorial likelihood approach, and provided a pathogenic or likely pathogenic classification for seven of the 12 spliceogenic variants. The apparent disparity between experimental evidence and the multifactorial predictions is likely due to several factors, including a paucity of likelihood information and a nonspecific prior probability applied for intronic variants outside the consensus dinucleotides. Development of prior probabilities of pathogenicity incorporating bioinformatic prediction of splicing aberrations should improve identification of functionally relevant variants and enhance multifactorial likelihood analysis of intronic variants.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Authors prepress title: "Identification of clinically significant splicing aberrations for intronic BRCA1 and BRCA2 sequence variants up to 12 nucleotides from the intron/exon boundary".

 
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Created: Thu, 20 Oct 2011, 14:13:34 EST by Assoc Prof Melissa Brown on behalf of School of Chemistry & Molecular Biosciences