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

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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-repair1,2. 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 incidence3,4. 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.

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We thank K. Redman, J. Gregory and J. Lipscombe for sample management in series 1 and 2; M.R. Stratton and J. Peto for access to the DNA samples in series 3; the NCCGP team at Westlakes Research Institute for the preparation of the newborn DNA samples, and at Newcastle University for providing the data; the physicians of the Children's and Women's Health Centre of British Columbia for the spontaneous abortion specimens; J. MacKay for facilitating the collaboration with Kuopio; and A. Trainer for helpful support. This work was funded by The Cancer Research Campaign (CRC) and Kuopio University Hospital EVO grant. Strangeways Research Laboratory has received a UK National Lottery Award. B.A.J.P. is a Gibb Fellow of the CRC.

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Correspondence to Catherine S. Healey.

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