Colombo, Mara ORCID: 0000-0001-5465-354X, Lopez-Perolio, Irene, Meeks, Huong D., Caleca, Laura ORCID: 0000-0002-3381-7493, Parsons, Michael T., Li, Hongyan, De Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B. Gomez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y., Varesco, Liliana ORCID: 0000-0003-4871-6668, Wappenschmidt, Barbara, Bolla, Manjeet K., Dennis, Joe, Michailidou, Kyriaki ORCID: 0000-0001-7065-1237, Wang, Qin, Aittomaki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker ORCID: 0000-0001-9320-8684, Beckmann, Matthias W., Beeghly-Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Bonanni, Bernardo, Brauch, Hiltrud ORCID: 0000-0001-7531-2736, Brenner, Hermann ORCID: 0000-0002-6129-1572, Burwinkel, Barbara, Chang-Claude, Jenny, Conroy, Don M., Couch, Fergus J., Cox, Angela ORCID: 0000-0002-5138-1099, Cross, Simon S., Czene, Kamila, Devilee, Peter, Dork, Thilo ORCID: 0000-0002-9458-0282, Eriksson, Mikael, Fasching, Peter A., Figueroa, Jonine, Fletcher, Olivia ORCID: 0000-0001-9387-7116, Flyger, Henrik, Gabrielson, Marike ORCID: 0000-0002-3171-1556, Garcia-Closas, Montserrat, Giles, Graham G., Gonzalez-Neira, Anna ORCID: 0000-0002-5421-2020, Guenel, Pascal ORCID: 0000-0002-8359-518X, Haiman, Christopher A., Hall, Per, Hamann, Ute, Hartman, Mikael ORCID: 0000-0001-5726-9965, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L., Jakubowska, Anna ORCID: 0000-0002-5650-0501, Jung, Audrey ORCID: 0000-0003-0875-6673, Kosma, Veli-Matti, Lambrechts, Diether ORCID: 0000-0002-3429-302X, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan ORCID: 0000-0003-2931-3003, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Olson, Janet E., Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Peto, Julian, Pylkas, Katri ORCID: 0000-0002-2449-0521, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., See, Mee Hoong ORCID: 0000-0002-3966-3368, Southey, Melissa C., Swerdlow, Anthony ORCID: 0000-0001-5550-4159, Teo, Soo H., Toland, Amanda E., Tomlinson, Ian, Truong, Therese, van Asperen, Christi J., van den Ouweland, Ans M. W., van der Kolk, Lizet E., Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, Dunning, Alison M., Easton, Douglas F., Henderson, Alex, Hogervorst, Frans B. L., Izatt, Louise, Offitt, Kenneth, Side, Lucy E., van Rensburg, Elizabeth J., McGuffog, Lesley, Antoniou, Antonis C., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Spurdle, Amanda B., Goldgar, David E., de la Hoya, Miguel ORCID: 0000-0002-8113-1410 and Radice, Paolo ORCID: 0000-0001-6298-4111 (2018). The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity. Hum. Mutat., 39 (5). S. 729 - 742. HOBOKEN: WILEY. ISSN 1098-1004

Full text not available from this repository.

Abstract

Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44x10(-115). There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Colombo, MaraUNSPECIFIEDorcid.org/0000-0001-5465-354XUNSPECIFIED
Lopez-Perolio, IreneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meeks, Huong D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caleca, LauraUNSPECIFIEDorcid.org/0000-0002-3381-7493UNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, HongyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Vecchi, GiovannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tudini, EmmaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foglia, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mondini, PatriziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behar, RaquelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garcia, Encarna B. GomezUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meindl, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niederacher, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Ane Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varesco, LilianaUNSPECIFIEDorcid.org/0000-0003-4871-6668UNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bolla, Manjeet K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dennis, JoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michailidou, KyriakiUNSPECIFIEDorcid.org/0000-0001-7065-1237UNSPECIFIED
Wang, QinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aittomaki, KristiinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anton-Culver, HodaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arndt, VolkerUNSPECIFIEDorcid.org/0000-0001-9320-8684UNSPECIFIED
Beckmann, Matthias W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beeghly-Fadel, AliciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benitez, JavierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boeckx, BramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bogdanova, Natalia V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojesen, Stig E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonanni, BernardoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brauch, HiltrudUNSPECIFIEDorcid.org/0000-0001-7531-2736UNSPECIFIED
Brenner, HermannUNSPECIFIEDorcid.org/0000-0002-6129-1572UNSPECIFIED
Burwinkel, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chang-Claude, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Conroy, Don M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cox, AngelaUNSPECIFIEDorcid.org/0000-0002-5138-1099UNSPECIFIED
Cross, Simon S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Czene, KamilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Devilee, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dork, ThiloUNSPECIFIEDorcid.org/0000-0002-9458-0282UNSPECIFIED
Eriksson, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fasching, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Figueroa, JonineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fletcher, OliviaUNSPECIFIEDorcid.org/0000-0001-9387-7116UNSPECIFIED
Flyger, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gabrielson, MarikeUNSPECIFIEDorcid.org/0000-0002-3171-1556UNSPECIFIED
Garcia-Closas, MontserratUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giles, Graham G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Neira, AnnaUNSPECIFIEDorcid.org/0000-0002-5421-2020UNSPECIFIED
Guenel, PascalUNSPECIFIEDorcid.org/0000-0002-8359-518XUNSPECIFIED
Haiman, Christopher A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hall, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartman, MikaelUNSPECIFIEDorcid.org/0000-0001-5726-9965UNSPECIFIED
Hauke, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollestelle, AntoinetteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jakubowska, AnnaUNSPECIFIEDorcid.org/0000-0002-5650-0501UNSPECIFIED
Jung, AudreyUNSPECIFIEDorcid.org/0000-0003-0875-6673UNSPECIFIED
Kosma, Veli-MattiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambrechts, DietherUNSPECIFIEDorcid.org/0000-0002-3429-302XUNSPECIFIED
Le Marchand, LoidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindblom, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lubinski, JanUNSPECIFIEDorcid.org/0000-0003-2931-3003UNSPECIFIED
Mannermaa, ArtoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Margolin, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miao, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milne, Roger L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhausen, Susan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevanlinna, HeliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Olson, Janet E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Peto, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pylkas, KatriUNSPECIFIEDorcid.org/0000-0002-2449-0521UNSPECIFIED
Sawyer, Elinor J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, Marjanka K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, Rita K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneeweiss, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoemaker, Minouk J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
See, Mee HoongUNSPECIFIEDorcid.org/0000-0002-3966-3368UNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swerdlow, AnthonyUNSPECIFIEDorcid.org/0000-0001-5550-4159UNSPECIFIED
Teo, Soo H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Truong, ThereseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Asperen, Christi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van den Ouweland, Ans M. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Kolk, Lizet E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winqvist, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yannoukakos, DrakoulisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zheng, WeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dunning, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Easton, Douglas F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henderson, AlexUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hogervorst, Frans B. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izatt, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Offitt, KennethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Side, Lucy E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Rensburg, Elizabeth J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McGuffog, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDorcid.org/0000-0002-1878-2587UNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDorcid.org/0000-0002-8113-1410UNSPECIFIED
Radice, PaoloUNSPECIFIEDorcid.org/0000-0001-6298-4111UNSPECIFIED
URN: urn:nbn:de:hbz:38-186952
DOI: 10.1002/humu.23411
Journal or Publication Title: Hum. Mutat.
Volume: 39
Number: 5
Page Range: S. 729 - 742
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNCLASSIFIED VARIANTS; FANCONI-ANEMIA; INTEGRATED EVALUATION; SEQUENCE VARIANTS; MUTATIONS; BREAST; RNA; INACTIVATION; RISK; PCRMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/18695

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