The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
Standard
The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity. / Colombo, Mara; Lòpez-Perolio, Irene; Meeks, Huong D; Caleca, Laura; Parsons, Michael T; Li, Hongyan; De Vecchi, Giovanna; Tudini, Emma; Foglia, Claudia; Mondini, Patrizia; Manoukian, Siranoush; Behar, Raquel; Garcia, Encarna B Gómez; Meindl, Alfons; Montagna, Marco; Niederacher, Dieter; Schmidt, Ane Y; Varesco, Liliana; Wappenschmidt, Barbara; Bolla, Manjeet K; Dennis, Joe; Michailidou, Kyriaki; Wang, Qin; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W; Beeghly-Fadel, Alicia; Benitez, Javier; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Chang-Claude, Jenny; Conroy, Don M; Couch, Fergus J; Cox, Angela; Cross, Simon S; Czene, Kamila; Devilee, Peter; Dörk, Thilo; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Fletcher, Olivia; Flyger, Henrik; Gabrielson, Marike; García-Closas, Montserrat; Giles, Graham G; González-Neira, Anna; Guénel, Pascal; Haiman, Christopher A; Hall, Per; Hamann, Ute; Hartman, Mikael; Hauke, Jan; Hollestelle, Antoinette; Hopper, John L; Jakubowska, Anna; Jung, Audrey; Kosma, Veli-Matti; Lambrechts, Diether; Le Marchand, Loid; Lindblom, Annika; Lubinski, Jan; Mannermaa, Arto; Margolin, Sara; Miao, Hui; Milne, Roger L; Neuhausen, Susan L; Nevanlinna, Heli; Olson, Janet E; Peterlongo, Paolo; Peto, Julian; Pylkäs, Katri; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; See, Mee Hoong; Southey, Melissa C; Swerdlow, Anthony; Teo, Soo H; Toland, Amanda E; Tomlinson, Ian; Truong, Thérèse; 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; Embrace, Study; Hebon, Study; McGuffog, Lesley; Antoniou, Antonis C; Chenevix-Trench, Georgia; Spurdle, Amanda B; Goldgar, David E; Hoya, Miguel de la; Radice, Paolo.
In: HUM MUTAT, Vol. 39, No. 5, 05.2018, p. 729-741.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
AU - Colombo, Mara
AU - Lòpez-Perolio, Irene
AU - Meeks, Huong D
AU - Caleca, Laura
AU - Parsons, Michael T
AU - Li, Hongyan
AU - De Vecchi, Giovanna
AU - Tudini, Emma
AU - Foglia, Claudia
AU - Mondini, Patrizia
AU - Manoukian, Siranoush
AU - Behar, Raquel
AU - Garcia, Encarna B Gómez
AU - Meindl, Alfons
AU - Montagna, Marco
AU - Niederacher, Dieter
AU - Schmidt, Ane Y
AU - Varesco, Liliana
AU - Wappenschmidt, Barbara
AU - Bolla, Manjeet K
AU - Dennis, Joe
AU - Michailidou, Kyriaki
AU - Wang, Qin
AU - Aittomäki, Kristiina
AU - Andrulis, Irene L
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Beckmann, Matthias W
AU - Beeghly-Fadel, Alicia
AU - Benitez, Javier
AU - Boeckx, Bram
AU - Bogdanova, Natalia V
AU - Bojesen, Stig E
AU - Bonanni, Bernardo
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Burwinkel, Barbara
AU - Chang-Claude, Jenny
AU - Conroy, Don M
AU - Couch, Fergus J
AU - Cox, Angela
AU - Cross, Simon S
AU - Czene, Kamila
AU - Devilee, Peter
AU - Dörk, Thilo
AU - Eriksson, Mikael
AU - Fasching, Peter A
AU - Figueroa, Jonine
AU - Fletcher, Olivia
AU - Flyger, Henrik
AU - Gabrielson, Marike
AU - García-Closas, Montserrat
AU - Giles, Graham G
AU - González-Neira, Anna
AU - Guénel, Pascal
AU - Haiman, Christopher A
AU - Hall, Per
AU - Hamann, Ute
AU - Hartman, Mikael
AU - Hauke, Jan
AU - Hollestelle, Antoinette
AU - Hopper, John L
AU - Jakubowska, Anna
AU - Jung, Audrey
AU - Kosma, Veli-Matti
AU - Lambrechts, Diether
AU - Le Marchand, Loid
AU - Lindblom, Annika
AU - Lubinski, Jan
AU - Mannermaa, Arto
AU - Margolin, Sara
AU - Miao, Hui
AU - Milne, Roger L
AU - Neuhausen, Susan L
AU - Nevanlinna, Heli
AU - Olson, Janet E
AU - Peterlongo, Paolo
AU - Peto, Julian
AU - Pylkäs, Katri
AU - Sawyer, Elinor J
AU - Schmidt, Marjanka K
AU - Schmutzler, Rita K
AU - Schneeweiss, Andreas
AU - Schoemaker, Minouk J
AU - See, Mee Hoong
AU - Southey, Melissa C
AU - Swerdlow, Anthony
AU - Teo, Soo H
AU - Toland, Amanda E
AU - Tomlinson, Ian
AU - Truong, Thérèse
AU - van Asperen, Christi J
AU - van den Ouweland, Ans M W
AU - van der Kolk, Lizet E
AU - Winqvist, Robert
AU - Yannoukakos, Drakoulis
AU - Zheng, Wei
AU - Dunning, Alison M
AU - Easton, Douglas F
AU - Henderson, Alex
AU - Hogervorst, Frans B L
AU - Izatt, Louise
AU - Offitt, Kenneth
AU - Side, Lucy E
AU - van Rensburg, Elizabeth J
AU - Embrace, Study
AU - Hebon, Study
AU - McGuffog, Lesley
AU - Antoniou, Antonis C
AU - Chenevix-Trench, Georgia
AU - Spurdle, Amanda B
AU - Goldgar, David E
AU - Hoya, Miguel de la
AU - Radice, Paolo
N1 - © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.
PY - 2018/5
Y1 - 2018/5
N2 - 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 7.44 × 10-115 . 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.
AB - 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 7.44 × 10-115 . 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.
KW - Journal Article
U2 - 10.1002/humu.23411
DO - 10.1002/humu.23411
M3 - SCORING: Journal article
C2 - 29460995
VL - 39
SP - 729
EP - 741
JO - HUM MUTAT
JF - HUM MUTAT
SN - 1059-7794
IS - 5
ER -