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The Mre11 complex, composed of RAD50, NBS1 and MRE11, has an essential role in the maintenance of genomic integrity and preventing cells from malignancy. Here we report the association of three Mre11 complex mutations with hereditary breast cancer susceptibility, studied by using a case–control design with 317 consecutive, newly diagnosed Northern Finnish breast cancer patients and 1000 geographically matched healthy controls (P =0.0004).RAD50687delT displayed significantly elevated frequency in the studied patients (8 out of 317, OR 4.3, 95% CI 1.5–12.5,P= 0.008), which indicates that it is a relatively common low-penetrance risk allele in this cohort. Haplotype analysis and the screening of altogether 512 additional breast cancer cases from Sweden, Norway and Iceland suggest thatRAD50687delT is a Finnish founder mutation, not present in the other Nordic cohorts. TheRAD50IVS3-1G&gt;A splicing mutation leading to translational frameshift was observed in one patient, and theNBS1Leu150Phe missense mutation affecting a conserved residue in the functionally important BRCA1 carboxy-terminal (BRCT) domain in two patients, both being absent from 1000 controls. Microsatellite marker analysis showed that loss of the wild-type allele was not involved in the tumorigenesis in any of the studied mutation carriers, but they all showed increased genomic instability assessed by cytogenetic analysis of peripheral blood T-lymphocytes (P= 0.006). In particular, the total number of chromosomal rearrangements was significantly increased (P= 0.002). These findings suggest an effect forRAD50andNBS1haploinsufficiency on genomic integrity and susceptibility to cancer.

RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability