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Title: The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
Authors: Colombo, M
Lòpez-Perolio, I
Meeks, H.D
Caleca, L
Parsons, M.T
Li, H
De Vecchi, G
Tudini, E
Foglia, C
Mondini, P
Manoukian, S
Behar, R
Garcia, E.B.G
Meindl, A
Montagna, M
Niederacher, D
Schmidt, A.Y
Varesco, L
Wappenschmidt, B
Bolla, M.K
Dennis, J
Michailidou, K
Wang, Q
Aittomäki, K
Andrulis, I.L
Anton-Culver, H
Arndt, V
Beckmann, M.W
Beeghly-Fadel, A
Benitez, J
Boeckx, B
Bogdanova, N.V
Bojesen, S.E
Bonanni, B
Brauch, H
Brenner, H
Burwinkel, B
Chang-Claude, J
Conroy, D.M
Couch, F.J
Cox, A
Cross, S.S
Czene, K
Devilee, P
Dörk, T
Eriksson, M
Fasching, P.A
Figueroa, J
Fletcher, O
Flyger, H
Gabrielson, M
García-Closas, M
Giles, G.G
González-Neira, A
Guénel, P
Haiman, C.A
Hall, P
Hamann, U
Hartman, M 
Hauke, J
Hollestelle, A
Hopper, J.L
Jakubowska, A
Jung, A
Kosma, V.-M
Lambrechts, D
Le Marchand, L
Lindblom, A
Lubinski, J
Mannermaa, A
Margolin, S
Miao, H 
Milne, R.L
Neuhausen, S.L
Nevanlinna, H
Olson, J.E
Peterlongo, P
Peto, J
Pylkäs, K
Sawyer, E.J
Schmidt, M.K
Schmutzler, R.K
Schneeweiss, A
Schoemaker, M.J
See, M.H
Southey, M.C
Swerdlow, A
Teo, S.H
Toland, A.E
Tomlinson, I
Truong, T
van Asperen, C.J
van den Ouweland, A.M.W
van der Kolk, L.E
Winqvist, R
Yannoukakos, D
Zheng, W
Dunning, A.M
Easton, D.F
Henderson, A
Hogervorst, F.B.L
Izatt, L
Offitt, K
Side, L.E
van Rensburg, E.J
Embrace, S
Hebon, S
McGuffog, L
Antoniou, A.C
Chenevix-Trench, G
Spurdle, A.B
Goldgar, D.E
Hoya, M.D.L
Radice, P
kConFab/AOCS Investigators
Seah, S
Keywords: BRCA1 protein
BRCA2 protein
complementary DNA
messenger RNA
BRCA2 protein
BRCA2 protein, human
messenger RNA
breast cancer
cancer inhibition
cancer risk
case control study
cell viability
controlled study
droplet digital polymerase chain reaction
gene frequency
gene mutation
genetic analysis
genetic risk
genetic screening
genetic transcription
genetic variation
human cell
lymphoblastoid cell line
major clinical study
multicenter study
percentage of viable cells
priority journal
protein function
qualitative analysis
quantitative analysis
real time polymerase chain reaction
segregation analysis
biological model
cell line
genetic predisposition
nucleotide sequence
RNA splicing
Base Sequence
BRCA2 Protein
Cell Line
Genetic Predisposition to Disease
Genetic Variation
Models, Genetic
RNA Splicing
RNA, Messenger
Issue Date: 2018
Publisher: John Wiley and Sons Inc.
Citation: Colombo, M, Lòpez-Perolio, I, Meeks, H.D, Caleca, L, Parsons, M.T, Li, H, De Vecchi, G, Tudini, E, Foglia, C, Mondini, P, Manoukian, S, Behar, R, Garcia, E.B.G, Meindl, A, Montagna, M, Niederacher, D, Schmidt, A.Y, Varesco, L, Wappenschmidt, B, Bolla, M.K, Dennis, J, Michailidou, K, Wang, Q, Aittomäki, K, Andrulis, I.L, Anton-Culver, H, Arndt, V, Beckmann, M.W, Beeghly-Fadel, A, Benitez, J, Boeckx, B, Bogdanova, N.V, Bojesen, S.E, Bonanni, B, Brauch, H, Brenner, H, Burwinkel, B, Chang-Claude, J, Conroy, D.M, Couch, F.J, Cox, A, Cross, S.S, Czene, K, Devilee, P, Dörk, T, Eriksson, M, Fasching, P.A, Figueroa, J, Fletcher, O, Flyger, H, Gabrielson, M, García-Closas, M, Giles, G.G, González-Neira, A, Guénel, P, Haiman, C.A, Hall, P, Hamann, U, Hartman, M, Hauke, J, Hollestelle, A, Hopper, J.L, Jakubowska, A, Jung, A, Kosma, V.-M, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Margolin, S, Miao, H, Milne, R.L, Neuhausen, S.L, Nevanlinna, H, Olson, J.E, Peterlongo, P, Peto, J, Pylkäs, K, Sawyer, E.J, Schmidt, M.K, Schmutzler, R.K, Schneeweiss, A, Schoemaker, M.J, See, M.H, Southey, M.C, Swerdlow, A, Teo, S.H, Toland, A.E, Tomlinson, I, Truong, T, van Asperen, C.J, van den Ouweland, A.M.W, van der Kolk, L.E, Winqvist, R, Yannoukakos, D, Zheng, W, Dunning, A.M, Easton, D.F, Henderson, A, Hogervorst, F.B.L, Izatt, L, Offitt, K, Side, L.E, van Rensburg, E.J, Embrace, S, Hebon, S, McGuffog, L, Antoniou, A.C, Chenevix-Trench, G, Spurdle, A.B, Goldgar, D.E, Hoya, M.D.L, Radice, P, kConFab/AOCS Investigators, Seah, S (2018). The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity. Human Mutation 39 (5) : 729-741. ScholarBank@NUS 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 7.44 × 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. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.
Source Title: Human Mutation
ISSN: 1059-7794
DOI: 10.1002/humu.23411
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