Fackenthal, James D., Yoshimatsu, Toshio ORCID: 0000-0003-2674-8159, Zhang, Bifeng, de Garibay, Gorka R., Colombo, Mara ORCID: 0000-0001-5465-354X, De Vecchi, Giovanna, Ayoub, Samantha C., Lal, Kumar, Olopade, Olufunmilayo I., Vega, Ana, Santamarina, Marta, Blanco, Ana, Wappenschmidt, Barbara, Becker, Alexandra, Houdayer, Claude, Walker, Logan C., Lopez-Perolio, Irene, Thomassen, Mads, Parsons, Michael ORCID: 0000-0003-3242-8477, Whiley, Phillip, Blok, Marinus J., Brandao, Rita D., Tserpelis, Demis, Baralle, Diana, Montalban, Gemma ORCID: 0000-0002-6958-4759, Gutierrez-Enriquez, Sara ORCID: 0000-0002-1711-6101, Diez, Orland, Lazaro, Conxi, Spurdle, Amanda B., Radice, Paolo ORCID: 0000-0001-6298-4111 and de la Hoya, Miguel ORCID: 0000-0002-8113-1410 (2016). Naturally occurring BRCA2 alternative mRNA splicing events in clinically relevant samples. J. Med. Genet., 53 (8). S. 548 - 559. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

Background BRCA1 and BRCA2 are the two principal tumour suppressor genes associated with inherited high risk of breast and ovarian cancer. Genetic testing of BRCA1/2 will often reveal one or more sequence variants of uncertain clinical significance, some of which may affect normal splicing patterns and thereby disrupt gene function. mRNA analyses are therefore among the tests used to interpret the clinical significance of some genetic variants. However, these could be confounded by the appearance of naturally occurring alternative transcripts unrelated to germline sequence variation or defects in gene function. To understand which novel splicing events are associated with splicing mutations and which are part of the normal BRCA2 splicing repertoire, a study was undertaken by members of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium to characterise the spectrum of naturally occurring BRCA2 mRNA alternate-splicing events. Methods mRNA was prepared from several blood and breast tissue-derived cells and cell lines by contributing ENIGMA laboratories. cDNA representing BRCA2 alternate splice sites was amplified and visualised using capillary or agarose gel electrophoresis, followed by sequencing. Results We demonstrate the existence of 24 different BRCA2 mRNA alternate-splicing events in lymphoblastoid cell lines and both breast cancer and non-cancerous breast cell lines. Conclusions These naturally occurring alternate-splicing events contribute to the array of cDNA fragments that may be seen in assays for mutation-associated splicing defects. Caution must be observed in assigning alternate-splicing events to potential splicing mutations.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fackenthal, James D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yoshimatsu, ToshioUNSPECIFIEDorcid.org/0000-0003-2674-8159UNSPECIFIED
Zhang, BifengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Garibay, Gorka R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Colombo, MaraUNSPECIFIEDorcid.org/0000-0001-5465-354XUNSPECIFIED
De Vecchi, GiovannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ayoub, Samantha C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olopade, Olufunmilayo I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Santamarina, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blanco, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houdayer, ClaudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walker, Logan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez-Perolio, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, MichaelUNSPECIFIEDorcid.org/0000-0003-3242-8477UNSPECIFIED
Whiley, PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blok, Marinus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandao, Rita D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tserpelis, DemisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baralle, DianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montalban, GemmaUNSPECIFIEDorcid.org/0000-0002-6958-4759UNSPECIFIED
Gutierrez-Enriquez, SaraUNSPECIFIEDorcid.org/0000-0002-1711-6101UNSPECIFIED
Diez, OrlandUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDorcid.org/0000-0002-8113-1410UNSPECIFIED
URN: urn:nbn:de:hbz:38-267628
DOI: 10.1136/jmedgenet-2015-103570
Journal or Publication Title: J. Med. Genet.
Volume: 53
Number: 8
Page Range: S. 548 - 559
Date: 2016
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BREAST/OVARIAN CANCER FAMILIES; UNCERTAIN SIGNIFICANCE; SEQUENCE VARIANTS; UNCLASSIFIED VARIANTS; FUNCTIONAL ASSAYS; DNA VARIANTS; MUTATIONS; CLASSIFICATION; PATHOGENICITY; GENESMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26762

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