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
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Creators: |
Creators | Email | ORCID | ORCID Put Code |
---|
Colombo, Mara | UNSPECIFIED | orcid.org/0000-0001-5465-354X | UNSPECIFIED | Lopez-Perolio, Irene | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Meeks, Huong D. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Caleca, Laura | UNSPECIFIED | orcid.org/0000-0002-3381-7493 | UNSPECIFIED | Parsons, Michael T. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Li, Hongyan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | De Vecchi, Giovanna | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Tudini, Emma | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Foglia, Claudia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Mondini, Patrizia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Manoukian, Siranoush | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Behar, Raquel | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Garcia, Encarna B. Gomez | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Meindl, Alfons | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Montagna, Marco | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Niederacher, Dieter | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schmidt, Ane Y. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Varesco, Liliana | UNSPECIFIED | orcid.org/0000-0003-4871-6668 | UNSPECIFIED | Wappenschmidt, Barbara | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bolla, Manjeet K. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Dennis, Joe | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Michailidou, Kyriaki | UNSPECIFIED | orcid.org/0000-0001-7065-1237 | UNSPECIFIED | Wang, Qin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Aittomaki, Kristiina | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Andrulis, Irene L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Anton-Culver, Hoda | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Arndt, Volker | UNSPECIFIED | orcid.org/0000-0001-9320-8684 | UNSPECIFIED | Beckmann, Matthias W. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Beeghly-Fadel, Alicia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Benitez, Javier | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Boeckx, Bram | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bogdanova, Natalia V. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bojesen, Stig E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Bonanni, Bernardo | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Brauch, Hiltrud | UNSPECIFIED | orcid.org/0000-0001-7531-2736 | UNSPECIFIED | Brenner, Hermann | UNSPECIFIED | orcid.org/0000-0002-6129-1572 | UNSPECIFIED | Burwinkel, Barbara | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Chang-Claude, Jenny | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Conroy, Don M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Couch, Fergus J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Cox, Angela | UNSPECIFIED | orcid.org/0000-0002-5138-1099 | UNSPECIFIED | Cross, Simon S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Czene, Kamila | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Devilee, Peter | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Dork, Thilo | UNSPECIFIED | orcid.org/0000-0002-9458-0282 | UNSPECIFIED | Eriksson, Mikael | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Fasching, Peter A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Figueroa, Jonine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Fletcher, Olivia | UNSPECIFIED | orcid.org/0000-0001-9387-7116 | UNSPECIFIED | Flyger, Henrik | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Gabrielson, Marike | UNSPECIFIED | orcid.org/0000-0002-3171-1556 | UNSPECIFIED | Garcia-Closas, Montserrat | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Giles, Graham G. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Gonzalez-Neira, Anna | UNSPECIFIED | orcid.org/0000-0002-5421-2020 | UNSPECIFIED | Guenel, Pascal | UNSPECIFIED | orcid.org/0000-0002-8359-518X | UNSPECIFIED | Haiman, Christopher A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hall, Per | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hamann, Ute | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hartman, Mikael | UNSPECIFIED | orcid.org/0000-0001-5726-9965 | UNSPECIFIED | Hauke, Jan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hollestelle, Antoinette | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hopper, John L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Jakubowska, Anna | UNSPECIFIED | orcid.org/0000-0002-5650-0501 | UNSPECIFIED | Jung, Audrey | UNSPECIFIED | orcid.org/0000-0003-0875-6673 | UNSPECIFIED | Kosma, Veli-Matti | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lambrechts, Diether | UNSPECIFIED | orcid.org/0000-0002-3429-302X | UNSPECIFIED | Le Marchand, Loid | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lindblom, Annika | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Lubinski, Jan | UNSPECIFIED | orcid.org/0000-0003-2931-3003 | UNSPECIFIED | Mannermaa, Arto | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Margolin, Sara | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Miao, Hui | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Milne, Roger L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Neuhausen, Susan L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Nevanlinna, Heli | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Olson, Janet E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Peterlongo, Paolo | UNSPECIFIED | orcid.org/0000-0001-6951-6855 | UNSPECIFIED | Peto, Julian | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Pylkas, Katri | UNSPECIFIED | orcid.org/0000-0002-2449-0521 | UNSPECIFIED | Sawyer, Elinor J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schmidt, Marjanka K. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schmutzler, Rita K. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schneeweiss, Andreas | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Schoemaker, Minouk J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | See, Mee Hoong | UNSPECIFIED | orcid.org/0000-0002-3966-3368 | UNSPECIFIED | Southey, Melissa C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Swerdlow, Anthony | UNSPECIFIED | orcid.org/0000-0001-5550-4159 | UNSPECIFIED | Teo, Soo H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Toland, Amanda E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Tomlinson, Ian | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Truong, Therese | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van Asperen, Christi J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van den Ouweland, Ans M. W. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van der Kolk, Lizet E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Winqvist, Robert | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Yannoukakos, Drakoulis | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Zheng, Wei | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Dunning, Alison M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Easton, Douglas F. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Henderson, Alex | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Hogervorst, Frans B. L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Izatt, Louise | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Offitt, Kenneth | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Side, Lucy E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | van Rensburg, Elizabeth J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | McGuffog, Lesley | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Antoniou, Antonis C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Chenevix-Trench, Georgia | UNSPECIFIED | orcid.org/0000-0002-1878-2587 | UNSPECIFIED | Spurdle, Amanda B. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | Goldgar, David E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | de la Hoya, Miguel | UNSPECIFIED | orcid.org/0000-0002-8113-1410 | UNSPECIFIED | Radice, Paolo | UNSPECIFIED | orcid.org/0000-0001-6298-4111 | UNSPECIFIED |
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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: |
Keywords | Language |
---|
UNCLASSIFIED VARIANTS; FANCONI-ANEMIA; INTEGRATED EVALUATION; SEQUENCE VARIANTS; MUTATIONS; BREAST; RNA; INACTIVATION; RISK; PCR | Multiple languages | Genetics & Heredity | Multiple languages |
|
Refereed: |
Yes |
URI: |
http://kups.ub.uni-koeln.de/id/eprint/18695 |
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