A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability

Inherited mutations in the gene BRCA2 predispose carriers to early onset br east cancer, but such mutations account for fewer than 2% of all cases in E ast Anglia. It is likely that low penetrance alleles explain the greater pa rt of inherited susceptibility to breast cancer; polymorphic variants in st rongly predisposing genes, such as BRCA2, are candidates for this role. BRC A2 is thought to be involved in DNA double strand break-repair(1,2) Few mic e 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( 3,4). Here we show that a common human polymorphism (N372H) in exon 10 of B RCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% Cl, 1.07-1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of hom ozygotes compared with that expected from Hardy-Weinberg equilibrium, where as in males there is an excess of homozygotes: the HH group has an estimate d 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.