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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 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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Healey, C., Dunning, A., Dawn Teare, M. et al. A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Nat Genet 26, 362–364 (2000).

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