Universität zu Köln

Wappenschmidt, Barbara, Becker, Alexandra A., Hauke, Jan, Weber, Ute, Engert, Stefanie, Koehler, Juliane, Kast, Karin, Arnold, Norbert ORCID: 0000-0003-4523-8808, Rhiem, Kerstin, Hahnen, Eric, Meindl, Alfons and Schmutzler, Rita K. (2012). Analysis of 30 Putative BRCA1 Splicing Mutations in Hereditary Breast and Ovarian Cancer Families Identifies Exonic Splice Site Mutations That Escape In Silico Prediction. PLoS One, 7 (12). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

Full text not available from this repository.

Abstract

Screening for pathogenic mutations in breast and ovarian cancer genes such as BRCA1/2, CHEK2 and RAD51C is common practice for individuals from high-risk families. However, test results may be ambiguous due to the presence of unclassified variants (UCV) in the concurrent absence of clearly cancer-predisposing mutations. Especially the presence of intronic or exonic variants within these genes that possibly affect proper pre-mRNA processing poses a challenge as their functional implications are not immediately apparent. Therefore, it appears necessary to characterize potential splicing UCV and to develop appropriate classification tools. We investigated 30 distinct BRCA1 variants, both intronic and exonic, regarding their spliceogenic potential by commonly used in silico prediction algorithms (HSF, MaxEntScan) along with in vitro transcript analyses. A total of 25 variants were identified spliceogenic, either causing/enhancing exon skipping or activation of cryptic splice sites, or both. Except from a single intronic variant causing minor effects on BRCA1 pre-mRNA processing in our analyses, 23 out of 24 intronic variants were correctly predicted by MaxEntScan, while HSF was less accurate in this cohort. Among the 6 exonic variants analyzed, 4 severely impair correct pre-mRNA processing, while the remaining two have partial effects. In contrast to the intronic alterations investigated, only half of the spliceogenic exonic variants were correctly predicted by HSF and/or MaxEntScan. These data support the idea that exonic splicing mutations are commonly disease-causing and concurrently prone to escape in silico prediction, hence necessitating experimental in vitro splicing analysis. Citation: Wappenschmidt B, Becker AA, Hauke J, Weber U, Engert S, et al. (2012) Analysis of 30 Putative BRCA1 Splicing Mutations in Hereditary Breast and Ovarian Cancer Families Identifies Exonic Splice Site Mutations That Escape In Silico Prediction. PLoS ONE 7(12): e50800. doi: 10.1371/journal.pone.0050800

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wappenschmidt, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Alexandra A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hauke, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Ute UNSPECIFIED UNSPECIFIED UNSPECIFIED Engert, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Kast, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Arnold, Norbert UNSPECIFIED orcid.org/0000-0003-4523-8808 UNSPECIFIED Rhiem, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Meindl, Alfons UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-476751
DOI:	10.1371/journal.pone.0050800
Journal or Publication Title:	PLoS One
Volume:	7
Number:	12
Date:	2012
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SEQUENCE VARIANTS; UNCLASSIFIED VARIANTS; SUSCEPTIBILITY GENE; MISSENSE MUTATIONS; GERMLINE MUTATIONS; HIGH PROPORTION; RNA; RISK; WOMEN; SUBSTITUTIONS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47675