Biallelic germline mutations in BRCA2 occur in the FA-D1 subtype of the rare pediatric disorder, Fanconi anemia (FA), characterized clinically by congenital abnormalities and a high propensity to develop malignancies early in life. Clinical and genetic data from 96 FA-D1 patients with biallelic BRCA2 mutations were collected and used to develop a new cancer risk prediction score system based on the specific mutations in BRCA2. This score takes into account the location of frameshift/stop and missense mutations relative to exon 11 of BRCA2, which encodes the major sites for interaction with the RAD51 recombinase, and uses the MaxEnt and HBond splicing scores to analyze potential splice site pertubations. Among 75 FA-D1 patients with ascertained BRCA2 mutations, 66 patients developed 102 malignancies, ranging from one to three independent tumors per individual. The median age at the manifestation of peripheral embryonal tumors was 1.0, of hematologic malignancies 1.8, and of CNS tumors 2.7 years, respectively. Patients who received treatment lived longer than those without. Using our novel scoring system, we could distinguish three distinct cancer risk groups among FA-D1 patients: in the first, patients developed their initial malignancy at a median age of 1.3 years (n = 36, 95% CI 0.9–1.8), in the second group at 2.3 years (n = 17, 95% CI 1.4–4.4) and in the 3rd group at 23.0 years (n = 22, 95% CI 4.3-n/a). Therefore, this scoring system allows, for the first time, to predict the cancer manifestation of FA-D1 patients simply based on the type and position of the mutations in BRCA2.