Evaluation of a 5-tier scheme proposed for classification of sequence variants using bioinformatic and splicing assay data: inter-reviewer variability and promotion of minimum reporting guidelines.
The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations.
A BRCA2 germline mutation (p.Ile2490Thr), previously reported in breast cancer and, as compound heterozygote, in Fanconi anemia, was identified in the 21-year-old patient diagnosed after pregnancy, negative for cancer family history.The tumor was not available for study.
Two other kindreds each contained a Fanconi anemia-afflicted child who developed medulloblastoma; one child was of Latin American ancestry and a compound heterozygote for BRCA2*I2490T/ 5301insA and the other was African American and a compound heterozygote for BRCA2*Q3066X/E1308X.
Remarkably, FA-AML1 cells appeared to lack the characteristic cellular FA phenotype, i.e., a hypersensitivity to growth inhibition and chromosomal breakage by the cross-linking agent mitomycin C. Genomic DNA from the patient showed biallelic mutations [8415G>T (K2729N)and 8732C>A (S2835STOP)] in the breast cancer susceptibility gene FANCD1/BRCA2 [N. Howlett et al., Science (Wash. DC), 297: 606-609, 2002].
Remarkably, FA-AML1 cells appeared to lack the characteristic cellular FA phenotype, i.e., a hypersensitivity to growth inhibition and chromosomal breakage by the cross-linking agent mitomycin C. Genomic DNA from the patient showed biallelic mutations [8415G>T (K2729N)and 8732C>A (S2835STOP)] in the breast cancer susceptibility gene FANCD1/BRCA2 [N. Howlett et al., Science (Wash. DC), 297: 606-609, 2002].
One kindred, of Ashkenazi Jewish ancestry, had five members who were diagnosed with breast cancer and two cousins who were BRCA2*6174delT/C3069X compound heterozygotes and had Fanconi anemia and brain tumors.