title: A missense mutation in the BRCA2 gene in three siblings with ovarian cancer.
abstract: Inherited susceptibility to ovarian cancer has been associated with germline defects at several loci. The major known ovarian cancer susceptibility gene is BRCA1 on chromosome 17q, which confers a risk of approximately 60% by the age of 70 years. Truncating mutations in BRCA2 on chromosome 13q also predispose to ovarian cancer, although they confer a lower risk than mutations in BRCA1. We have studied the molecular basis of ovarian cancer predisposition in a Finnish family with three affected sisters. Analysis of polymorphic markers provided evidence against linkage to BRCA1, but the sibship was consistent with linkage to BRCA2. Conformation-sensitive gel electrophoresis was used to screen the entire coding sequence of BRCA2. A G to A transition at nucleotide 8702 was observed, which is predicted to convert glycine 2901 to aspartate in the encoded protein. This sequence variant was not detected in 220 cancer-free Finnish control individuals, or in several hundred cancer families of many nationalities previously screened for BRCA2 mutations. Taken together with the fact that this amino acid residue and the surrounding region of BRCA2 is identical in mouse and chicken, the data suggest that this alteration is a disease-causing BRCA2 missense mutation. Previously published data indicate that the risks of breast and ovarian cancer conferred by BRCA2-truncating mutations varies with the position of the mutation in the gene. The missense mutation reported here suggests that the BRCA2 domain including and surrounding glycine 2901 may be more important in preventing neoplastic transformation in ovarian epithelium than in breast epithelium.
authors.affiliation: Haartman Institute, Department of Medical Genetics, University of Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Roth
authors.forename: P
authors.initials: P
authors.lastname: Kristo
authors.forename: A
authors.initials: A
authors.lastname: Auranen
authors.forename: M
authors.initials: M
authors.lastname: Shayehgi
authors.forename: S
authors.initials: S
authors.lastname: Seal
authors.forename: N
authors.initials: N
authors.lastname: Collins
authors.forename: R
authors.initials: R
authors.lastname: Barfoot
authors.forename: N
authors.initials: N
authors.lastname: Rahman
authors.forename: P J
authors.initials: PJ
authors.lastname: Klemi
authors.forename: S
authors.initials: S
authors.lastname: Grénman
authors.forename: L
authors.initials: L
authors.lastname: Sarantaus
authors.forename: H
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: R
authors.initials: R
authors.lastname: Butzow
authors.forename: A
authors.initials: A
authors.lastname: Ashworth
authors.forename: M R
authors.initials: MR
authors.lastname: Stratton
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D024682:BRCA2 Protein; D002645:Chickens; D018283:Cystadenocarcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009679:Nuclear Family; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; D017931:DNA Primers; D005819:Genetic Markers; D009363:Neoplasm Proteins; D014157:Transcription Factors