TY - JOUR
T1 - The BRCA2 c.68-7T > A variant is not pathogenic
T2 - 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 - kConFab/AOCS Investigators
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 - BRCA2 Protein/genetics
KW - Base Sequence
KW - Calibration
KW - Cell Line
KW - Exons/genetics
KW - Female
KW - Genetic Predisposition to Disease
KW - Genetic Variation
KW - Humans
KW - Mitomycin/pharmacology
KW - Models, Genetic
KW - RNA Splicing/genetics
KW - RNA, Messenger/genetics
U2 - 10.1002/humu.23411
DO - 10.1002/humu.23411
M3 - Journal article
C2 - 29460995
SN - 1059-7794
VL - 39
SP - 729
EP - 741
JO - Human Mutation
JF - Human Mutation
IS - 5
ER -
