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Human Molecular Genetics, 2003, Vol. 12, No. 8 915-923
DOI: 10.1093/hmg/ddg102
© 2003 Oxford University Press

A naturally occurring mutation in an ATP-binding domain of the recombination repair gene XRCC3 ablates its function without causing cancer susceptibility

Saeed Rafii1, Annika Lindblom2, Malcolm Reed3, Mark Meuth1 and Angela Cox1,*

1Institute for Cancer Studies, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK, 2 Department Molecular Medicine, Karolinska Institute, S17176 Stockholm, Sweden and 3Academic Unit of Surgical Oncology, Division of Clinical Sciences (South), University of Sheffield Medical School, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK

Received January 16, 2003; Accepted February 12, 2003

Inherited mutations of the BRCA1 and BRCA2 genes, whose protein products are necessary for the homology-directed DNA repair pathway, confer a dominant susceptibility to cancer. We have investigated whether mutations of genes encoding other components of the same DNA repair pathway can also affect cancer susceptibility. We have identified three novel non-synonymous substitutions in one such gene, encoding the RAD51-related protein XRCC3. One of these variants, D213N, occurs in a highly conserved ATP-binding domain and completely abrogates the ability of the transfected gene to correct the phenotype of XRCC3 deficient cells. The D213N variant was found in the heterozygous state in DNA from 3/1577 healthy individuals. However, we did not detect this variant at all amongst 187 breast cancer families and 1300 unrelated patients with common cancers. Thus we have no evidence that D213N increases the risk of cancer. We propose that not all components of the homologous recombination repair complex can act as cancer susceptibility genes.

* To whom correspondence should be addressed. Tel: +44 1142712373; Fax: +44 1142713515; Email: a.cox{at}shef.ac.uk


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