title: A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability.
abstract: Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.
authors.affiliation: CRC Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK. katie.healey@srl.cam.ac.uk
authors.forename: C S
authors.initials: CS
authors.lastname: Healey
authors.forename: A M
authors.initials: AM
authors.lastname: Dunning
authors.forename: M D
authors.initials: MD
authors.lastname: Teare
authors.forename: D
authors.initials: D
authors.lastname: Chase
authors.forename: L
authors.initials: L
authors.lastname: Parker
authors.forename: J
authors.initials: J
authors.lastname: Burn
authors.forename: J
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: A
authors.initials: A
authors.lastname: Mannermaa
authors.forename: V
authors.initials: V
authors.lastname: Kataja
authors.forename: D G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: P D
authors.initials: PD
authors.lastname: Pharoah
authors.forename: R N
authors.initials: RN
authors.lastname: Luben
authors.forename: D F
authors.initials: DF
authors.lastname: Easton
authors.forename: B A
authors.initials: BA
authors.lastname: Ponder
mesh_terms: D000483:Alleles; D000818:Animals; D024682:BRCA2 Protein; D001724:Birth Weight; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D004260:DNA Repair; D005091:Exons / Q000235:genetics; D005260:Female; D005313:Fetal Death / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000453:epidemiology / Q000235:genetics*; D016017:Odds Ratio; D012306:Risk; D012737:Sex Factors; D012744:Sex Ratio; D016037:Single-Blind Method; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors