Fanconi Anemia
In 2 brothers with Fanconi anemia complementation group D1 (FANCD1; 605724), Hirsch et al. (2004) identified compound heterozygosity for mutations in the BRCA2 gene: a 2-bp deletion in exon 8 (886delGT), inherited from the father, and an 8447T-A transversion in exon 18, resulting in a leu2740-to-ter substitution (L2740X; 600185.0028), inherited from the mother.
Wilms Tumor/Medulloblastoma/Glioblastoma
In 2 brothers who developed Wilms tumor (WT1; 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: a paternally inherited 886delGT, predicted to truncate the protein at codon 223 before the 8 BRC repeats, and a maternally inherited 5873C-A transversion in exon 11, resulting in a ser1882-to-ter substitution (S1882X; 600185.0031) predicted to truncate the protein such that BRC7 and BRC8 would be missing. One boy developed a glioblastoma (GLM3; 613029); the other had recurrent medulloblastoma (MDB; 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48.
Alter et al. (2007) included this mutation in an analysis of the clinical and molecular features associated with the BRCA2 mutations identified in FANCD1 patients. They noted that the 886delGT mutation is associated with brain tumors. They also concluded that small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, with early onset and high rates of leukaemia and specific solid tumours. These features may comprise an extreme variant of Fanconi anemia.
