title: A comprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay.
abstract: Biallelic mutations in the human breast cancer susceptibility gene, BRCA2, are associated with Fanconi anemia, implying that some persons who inherit 2 deleterious variants of BRCA2 are able to survive even though it is well established that BRCA2 is indispensable for viability in mice. One such variant, IVS7 + 2T > G, results in premature protein truncation because of skipping of exon 7. Surprisingly, the persons who are either IVS7 + 2T > G homozygous or compound heterozygous are born alive but die of malignancy associated with Fanconi anemia. Using a mouse embryonic stem cell-based functional assay, we found that the IVS7 + 2T > G allele produces an alternatively spliced transcript lacking exons 4-7, encoding an in-frame BRCA2 protein with an internal deletion of 105 amino acids (BRCA2(Δ105)). We demonstrate that BRCA2(Δ105) is proficient in homologous recombination-mediated DNA repair as measured by different functional assays. Evaluation of this transcript in normal and leukemia cells suggests that BRCA2(Δ105) may contribute to the viability of persons inheriting this mutation. In this study, we have also characterized 5 other BRCA2 variants and found 3 of these (p.L2510P, p.R2336H, and p.W2626C) to be deleterious and 2 (p.I2490T and p.K2729N) probably neutral. Such studies are important to understand the functional significance of unclassified BRCA2 variants.
authors: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors: Kajal
authors: K
authors: Biswas
authors: Ranabir
authors: R
authors: Das
authors: Blanche P
authors: BP
authors: Alter
authors: Sergey G
authors: SG
authors: Kuznetsov
authors: Stacey
authors: S
authors: Stauffer
authors: Susan L
authors: SL
authors: North
authors: Sandra
authors: S
authors: Burkett
authors: Lawrence C
authors: LC
authors: Brody
authors: Stefan
authors: S
authors: Meyer
authors: R Andrew
authors: RA
authors: Byrd
authors: Shyam K
authors: SK
authors: Sharan
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D053595:Embryonic Stem Cells; D005091:Exons / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics*; D024522:Genes, BRCA2; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D051379:Mice; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion; D012689:Sequence Homology, Nucleic Acid
chemical_list: D022821:RNA Splice Sites