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

Y1 - 2018

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

VL - 39

SP - 729

EP - 741

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 5

ER -