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Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

Background: Fanconi anemia is an inherited genomic instability syndrome associated with progressive bone marrow failure leading to death or the requirement for hematopoietic stem cell transplantation, acute myeloid leukemia, and solid tumors. Prior epidemiological studies have quantified the risks of bone marrow failure, acute myeloid leukemia and solid tumors, but these estimates have not been replicated., Design and Methods: We assembled a cohort of 181 patients with Fanconi anemia mostly from Germany. We calculated the ratio of observed to expected cancers, and the risks of bone marrow failure, acute myeloid leukemia, and solid tumors by age., Results: The first adverse event was bone marrow failure in 66 patients, acute meyloid leukemia in 14 patients and solid tumors in 10 patients. The ratio of observed to expected cancers was 44 for all cancers, 26 for all solid tumors, and 868 for acute myeloid leukemia; these increased risks were statistically significant. Significantly elevated ratios of observed to expected cancers were observed for esophageal (6281), vulvar (2411), head and neck (240), breast (34) and brain (23) tumors. Absent or abnormal radii, and a five-item congenital abnormality score, were significant risk factors for bone marrow failure. The cumulative incidence of bone marrow failure by the age of 10 years varied from 12.6% in the lowest bone marrow failure risk group to 84% in the highest. The relative hazard of bone marrow failure was significantly higher in complementation group G versus A (relative hazard=2.2) and in C versus A (relative hazard=5.4)., Conclusions: Findings from the German Fanconi Anemia Registry cohort validate prior risk estimates, and strongly support the concept that Fanconi anemia is a highly penetrant cancer susceptibility syndrome with early onset of acute myeloid leukemia and slightly later onset of specific solid tumors.

Fanconi's anaemia (FA) shows great variability in phenotypic symptoms. We report on two FA siblings of German ancestry with the very rare form of the complementation group FA-D. Both presented with a similar phenotype and mild disease severity but with different growth. In the sister, growth velocity was normal, puberty and menarche occurred spontaneously. Her final height was within her parental target height. The younger brother had a reduced growth velocity, height SDS values below -5.5 SDS, a markedly retarded bone age, and delayed puberty. At the age of 12.9 years, growth hormone deficiency (GHD) was diagnosed and treatment with growth hormone was initiated. Our cases emphasize the heterogeneity of symptoms in FA even in siblings with the same genotype. In FA-children with severe growth retardation, GHD must also be considered., (Copyright 2000 Harcourt Publishers Ltd.)

Fanconi anaemia (FA) is an autosomal recessive chromosomal instability disorder with extensive genetic heterogeneity. We determined the genetic subtypes in 28 ethnically and clinically unselected FA patients from Germany and The Netherlands, by complementation analysis. All five currently known complementation analysis. All five currently known complementation groups (FA-A to FA-E) appeared to be represented in the sample studied. The distribution of subtypes differed markedly in the two countries: FA-A patients were most prevalent in Germany (13/22, 59%), whereas in The Netherlands, the majority of patients were FA-C (4/6, 67%). This geographical inhomogeneity has implications for mutation-screening strategies in European FA patients.