title: A novel splice site mutation in the noncoding region of BRCA2: implications for Fanconi anemia and familial breast cancer diagnostics.
abstract: Fanconi anemia (FA) is a rare recessive disorder with chromosomal instability, congenital abnormalities, and a high cancer risk. The breast cancer susceptibility gene BRCA2 (FANCD1) is one of the 16 genes involved in this recessive disease. We have identified a novel mutation of the splice donor site of intron 1 in the noncoding region of BRCA2 in a Japanese FA family. This mutation may account for the FA phenotype in a patient originally reported to have biallelic mutations in BRCA2. Subsequent functional studies revealed that one of the mutations, K2729N, was a neutral change. As reported here, a more careful analysis resulted in the identification of a novel splice site mutation. Functional analysis using a mouse embryonic stem cell-based assay revealed that it causes aberrant splicing, reduced transcript levels and hypersensitivity to DNA damaging agents, suggesting that it is likely to be pathogenic. Although similar pathogenic variants in the noncoding region of BRCA1 and 2 were not identified in a cohort of 752 familial breast cancer cases, we still think this finding is relevant for mutation analysis in Hereditary Breast and Ovarian Cancer Syndrome families in a diagnostic setting.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Janine L
authors.initials: JL
authors.lastname: Bakker
authors.forename: Eswary
authors.initials: E
authors.lastname: Thirthagiri
authors.forename: Saskia E
authors.initials: SE
authors.lastname: van Mil
authors.forename: Muriel A
authors.initials: MA
authors.lastname: Adank
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ikeda
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
authors.forename: Johan P
authors.initials: JP
authors.lastname: de Winter
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Sharan
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
mesh_terms: D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005199:Fanconi Anemia / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D022821:RNA Splice Sites
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D022821:RNA Splice Sites
keywords: BRCA2; Fanconi anemia; aberrant splicing; familial breast cancer