title: A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing.
abstract: Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G>A (c.7617+1G>A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West Denmark, while it is rare in Central and East Denmark and not identified in South Sweden. Haplotype analysis using dense SNP arrays indicated a common founder of the mutation approximately 1,500 years ago.
authors.affiliation: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. mads.thomassen@ouh.regionsyddanmark.dk
authors.forename: Mads
authors.initials: M
authors.lastname: Thomassen
authors.forename: Inge Søkilde
authors.initials: IS
authors.lastname: Pedersen
authors.forename: Ida
authors.initials: I
authors.lastname: Vogel
authors.forename: Thomas V O
authors.initials: TV
authors.lastname: Hansen
authors.forename: Charlotte
authors.initials: C
authors.lastname: Brasch-Andersen
authors.forename: Claus L
authors.initials: CL
authors.lastname: Brasen
authors.forename: Dorthe
authors.initials: D
authors.lastname: Crüger
authors.forename: Lone
authors.initials: L
authors.lastname: Sunde
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
authors.forename: Uffe B
authors.initials: UB
authors.lastname: Jensen
authors.forename: Marie Luise
authors.initials: ML
authors.lastname: Bisgaard
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Gerdes
authors.forename: Torben A
authors.initials: TA
authors.lastname: Kruse
mesh_terms: D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D003718:Denmark / Q000453:epidemiology; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*; D012016:Reference Values
chemical_list: D022821:RNA Splice Sites