Journal Article

Counting potentially functional variants in <i>BRCA1</i>, <i>BRCA2</i> and <i>ATM</i> predicts breast cancer susceptibility

Nichola Johnson, Olivia Fletcher, Claire Palles, Matthew Rudd, Emily Webb, Gabrielle Sellick, Isabel dos Santos Silva, Valerie McCormack, Lorna Gibson, Agnes Fraser, Angela Leonard, Clare Gilham, Sean V. Tavtigian, Alan Ashworth, Richard Houlston and Julian Peto

in Human Molecular Genetics

Volume 16, issue 9, pages 1051-1057
Published in print May 2007 | ISSN: 0964-6906
Published online March 2007 | e-ISSN: 1460-2083 | DOI:
Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility

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Rare inactivating mutations in BRCA1, BRCA2, ATM, TP53 and CHEK2 confer relative risks for breast cancer between about 2 and more than 10, but more common variants in these genes are generally considered of little or no clinical significance. Under the polygenic model for breast cancer carriers of multiple low-penetrance alleles are at high risk, but few such alleles have been reliably identified. We analysed 1037 potentially functional single nucleotide polymorphisms (SNPs) in candidate cancer genes in 473 women with two primary breast cancers and 2463 controls. Twenty-five of these SNPs were in BRCA1, BRCA2, ATM, TP53 and CHEK2. Among the 1037 SNPs there were a few significant findings, but hardly more than would be expected in this large experiment. There was, however, a significant trend in risk with increasing numbers of variant alleles for the 25 SNPs in BRCA1, BRCA2, ATM, TP53 and CHEK2 (Ptrend = 0.005). For the 21 of these with minor allele frequency <10% this trend was highly significant (Ptrend = 0.00004, odds ratio for 3 or more SNPs = 2.90, 95% CI 1.69–4.97). The individual effects of most of these risk alleles were undetectably small even in this well powered study, but the risk conferred by multiple variants is readily detectable and makes a substantial contribution to susceptibility. A risk score incorporating a suitably weighted sum of all potentially functional variants in these and a few other candidate genes may provide clinically useful identification of women at high genetic risk.

Journal Article.  4438 words.  Illustrated.

Subjects: Genetics and Genomics

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