In Western Europe and the United States approximately 1 in 12 women develop breast cancer. A small proportion of breast cancer cases, in particular those arising at a young age, are attributable to a highly penetrant, autosomal dominant predisposition to the disease. The breast cancer susceptibility gene, BRCA2, was recently localized to chromosome 13q12-q13. Here we report the identification of a gene in which we have detected six different germline mutations in breast cancer families that are likely to be due to BRCA2. Each mutation causes serious disruption to the open reading frame of the transcriptional unit. The results indicate that this is the BRCA2 gene.

PALB2 interacts with BRCA2, and biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia. We identified monoallelic truncating PALB2 mutations in 10/923 individuals with familial breast cancer compared with 0/1,084 controls (P = 0.0004) and show that such mutations confer a 2.3-fold higher risk of breast cancer (95% confidence interval (c.i.) = 1.4-3.9, P = 0.0025). The results show that PALB2 is a breast cancer susceptibility gene and further demonstrate the close relationship of the Fanconi anemia-DNA repair pathway and breast cancer predisposition. PALB2 (for 'partner and localizer of BRCA2') encodes a recently discovered protein that interacts with BRCA2, is implicated in its nuclear localization and stability and is required for some functions of BRCA2 in homologous recombination and double-strand break repair1. In a paper in this issue, we show that biallelic PALB2 mutations are responsible for a subset of Fanconi anemia cases characterized by a phenotype similar to that caused by biallelic BRCA2 mutations2. Prompted by these observations, we investigated whether monoallelic PALB2 mutations confer susceptibility to breast cancer by sequencing the gene © 2007 Nature Publishing Group Correspondence should be addressed to N.R (nazneen.rahman@icr.ac.uk).. AUTHOR CONTRIBUTIONS The study was designed by N.R. and M.R.S. The molecular analyses were performed by S.S., P.K., A.R., S.R., K.S., R.B., T.C., H.J. and S.H. under the direction of N.R. The statistical analyses were performed by D.T., A.E. and L.M. under the direction of D.F.E. The familial collections were initiated by D.G.E. and D.E. and were collected by the Breast Cancer Susceptibility Collaboration (UK). The manuscript was written by N.R. and M.R.S.Note: Supplementary information is available on the Nature Genetics website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We identified truncating PALB2 mutations in 10/923 (1.1%) independently ascertained individuals with familial breast cancer from separate families compared with 0/1,084 (0%) controls (P = 0.0004) ( Table 1 and Fig. 1a). Nine of the PALB2 mutations were in the 908 families with female breast cancer only (1.0%). One occurred in the 15 families (6.7%) with cases of both female and male breast cancer (P = 0.15). Although this observation requires further investigation, it suggests that PALB2 mutations may confer a higher relative risk of male breast cancer than female breast cancer, and BRCA2 mutations are known to confer a high relative risk of male breast cancer3. One proband with a PALB2 mutation developed melanoma at 47 years of age in addition to breast cancer at 56 years. Apart from this individual, there were no other malignancies other than breast cancer in individuals with PALB2 mutations. Two of four first-degree affected relatives of probands with PALB2 mutations also carried a PALB2 mutation. This pattern of incomplete segregation in affected relatives is typical of s...

Familial cylindromatosis is an autosomal dominant genetic predisposition to multiple tumours of the skin appendages. The susceptibility gene (CYLD) has previously been localized to chromosome 16q and has the genetic attributes of a tumour-suppressor gene (recessive oncogene). Here we have identified CYLD by detecting germline mutations in 21 cylindromatosis families and somatic mutations in 1 sporadic and 5 familial cylindromas. All mutations predict truncation or absence of the encoded protein. CYLD encodes three cytoskeletal-associated-protein-glycine-conserved (CAP-GLY) domains, which are found in proteins that coordinate the attachment of organelles to microtubules. CYLD also has sequence homology to the catalytic domain of ubiquitin carboxy-terminal hydrolases (UCH).

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