Detection of Splicing Aberrations Caused by BRCA1 and BRCA2 Sequence Variants Encoding Missense Substitutions: Implications for Prediction of Pathogenicity

Walker, Logan C., Whiley, Phillip J., Couch, Fergus J., Farrugia, Daniel J., Healey, Sue, Eccles, Diana M., Lin, Feng, Butler, Samantha A., Goff, Sheila A., Thompson, Bryony A., Lakhani, Sunil R., Da Silva, Leonard M., Tavtigian, Sean V., Goldgar, David E., Brown, Melissa A. and Spurdle, Amanda B. (2010) Detection of Splicing Aberrations Caused by BRCA1 and BRCA2 Sequence Variants Encoding Missense Substitutions: Implications for Prediction of Pathogenicity. Human Mutation, 31 6: E1484-E1505. doi:10.1002/humu.21267

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Author Walker, Logan C.
Whiley, Phillip J.
Couch, Fergus J.
Farrugia, Daniel J.
Healey, Sue
Eccles, Diana M.
Lin, Feng
Butler, Samantha A.
Goff, Sheila A.
Thompson, Bryony A.
Lakhani, Sunil R.
Da Silva, Leonard M.
Tavtigian, Sean V.
Goldgar, David E.
Brown, Melissa A.
Spurdle, Amanda B.
Title Detection of Splicing Aberrations Caused by BRCA1 and BRCA2 Sequence Variants Encoding Missense Substitutions: Implications for Prediction of Pathogenicity
Journal name Human Mutation   Check publisher's open access policy
ISSN 1098-1004
1059-7794
Publication date 2010-06
Sub-type Article (original research)
DOI 10.1002/humu.21267
Volume 31
Issue 6
Start page E1484
End page E1505
Total pages 22
Place of publication New York
Publisher Wiley-Liss
Collection year 2011
Language eng
Formatted abstract
Missense substitutions in high-risk cancer susceptibility genes create clinical uncertainty in the genetic counseling process. Multifactorial likelihood classification approaches and in vitro assays are useful for the classification of exonic sequence variants in BRCA1 and BRCA2, but these currently rely on the assumption that changes in protein function are the major biological mechanism of pathogenicity. This study investigates the potentially pathogenic role of aberrant splicing for exonic variants predicted to encode missense substitutions using patientderived RNA. No splicing aberrations were identified for BRCA1c.5054C>T and BRCA2c.7336A>G, c.8839G>A, and c.9154C>T. However, RT-PCR analysis identified a major splicing aberration for BRCA1c.4868C>G(p.Ala1623Gly), a variant encoding a missense substitution considered likely to be neutral. Splicing aberrations were also observed for BRCA2c.7988A>T(p.Glu2663Val) and c.8168A>G(p.Asp2723Gly), but both variant and wildtype alleles were shown to be present in full-length mRNA transcripts, suggesting that variant protein may be translated. BRCA2 protein function assays indicated that BRCA2p.Glu2663Val, p.Asp2723Gly and p.Arg3052Trp missense proteins have abrogated function consistent with pathogenicity. Multifactorial likelihood analysis provided evidence for pathogenicity for BRCA1 c.5054C>T(p.Thr1685Ile) and BRCA2c.7988A>T(p.Glu2663Val), c.8168A>G(p.Asp2723Gly) and c.9154C>T(p.Arg3052Trp), supporting experimentally derived evidence. These findings highlight the need for improved bioinformatic prediction of splicing aberrations and to refine multifactorial likelihood models used to assess clinical significance. ©2010 Wiley-Liss, Inc.
Keyword Brca1
Brca2
Clinical Significance
Variants
Splicing
Unknown Clinical-significance
Familial Breast-cancer
Antisense Oligonucleotides
Uncertain Significance
Unclassified variants
Estrogen-receptor
Dna-repair
Classification
Mutations
Risk
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 10 MAY 2010

 
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Created: Sun, 01 Aug 2010, 00:06:46 EST