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

A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability. Healey, C., S., Dunning, A., M., Teare, M., D., Chase, D., Parker, L., Burn, J., Chang-Claude, J., Mannermaa, A., Kataja, V., Huntsman, D., G., Pharoah, P., D., Luben, R., N., Easton, D., F., & Ponder, B., A. Nat Genet, 26(3):362-4., 2000.

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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-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.

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 title = {A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability},
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 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.},
 bibtype = {article},
 author = {Healey, C S and Dunning, A M and Teare, M D and Chase, D and Parker, L and Burn, J and Chang-Claude, J and Mannermaa, A and Kataja, V and Huntsman, D G and Pharoah, P D and Luben, R N and Easton, D F and Ponder, B A},
 journal = {Nat Genet},
 number = {3}
}

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