title: Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.
abstract: Several BRCA1 mutations have now been found to occur in geographically diverse breast and ovarian cancer families. To investigate mutation origin and mutation-specific phenotypes due to BRCA1, we constructed a haplotype of nine polymorphic markers within or immediately flanking the BRCA1 locus in a set of 61 breast/ovarian cancer families selected for having one of six recurrent BRCA1 mutations. Tests of both mutations and family-specific differences in age at diagnosis were not significant. A comparison of the six mutations in the relative proportions of cases of breast and ovarian cancer was suggestive of an effect (P = .069), with 57% of women presumed affected because of the 1294 del 40 BRCA1 mutation having ovarian cancer, compared with 14% of affected women with the splice-site mutation in intron 5 of BRCA1. For the BRCA1 mutations studied here, the individual mutations are estimated to have arisen 9-170 generations ago. In general, a high degree of haplotype conservation across the region was observed, with haplotype differences most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. For several of the instances, there was evidence for multiple, independent, BRCA1 mutational events.
authors.affiliation: Department of Medical Informatics, University of Utah School of Medicine, Salt Lake City 84108, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: S
authors.initials: S
authors.lastname: Mazoyer
authors.forename: L
authors.initials: L
authors.lastname: Friedman
authors.forename: M
authors.initials: M
authors.lastname: Stratton
authors.forename: K
authors.initials: K
authors.lastname: Offit
authors.forename: A
authors.initials: A
authors.lastname: Caligo
authors.forename: G
authors.initials: G
authors.lastname: Tomlinson
authors.forename: L
authors.initials: L
authors.lastname: Cannon-Albright
authors.forename: T
authors.initials: T
authors.lastname: Bishop
authors.forename: D
authors.initials: D
authors.lastname: Kelsell
authors.forename: E
authors.initials: E
authors.lastname: Solomon
authors.forename: B
authors.initials: B
authors.lastname: Weber
authors.forename: F
authors.initials: F
authors.lastname: Couch
authors.forename: J
authors.initials: J
authors.lastname: Struewing
authors.forename: P
authors.initials: P
authors.lastname: Tonin
authors.forename: F
authors.initials: F
authors.lastname: Durocher
authors.forename: S
authors.initials: S
authors.lastname: Narod
authors.forename: M H
authors.initials: MH
authors.lastname: Skolnick
authors.forename: G
authors.initials: G
authors.lastname: Lenoir
authors.forename: O
authors.initials: O
authors.lastname: Serova
authors.forename: B
authors.initials: B
authors.lastname: Ponder
authors.forename: D
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.forename: D
authors.initials: D
authors.lastname: Easton
authors.forename: M C
authors.initials: MC
authors.lastname: King
authors.forename: D E
authors.initials: DE
authors.lastname: Goldgar
mesh_terms: D000483:Alleles; D019313:BRCA1 Protein; D001943:Breast Neoplasms / Q000235:genetics; D002874:Chromosome Mapping; D005192:Family Health; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; D005819:Genetic Markers; D009363:Neoplasm Proteins; D014157:Transcription Factors