Acomprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay

Kajal Biswas, Ranabir Das, Blanche P. Alter, Sergey G. Kuznetsov, Stacey Stauffer, Susan L. North, Sandra Burkett, Lawrence C. Brody, Stefan Meyer, R. Andrew Byrd, Shyam K. Sharan

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


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 > Ghomozygous 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 (BRCA2Δ105). We demonstrate that BRCA2Δ105 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 BRCA2Δ105 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.

Original languageEnglish (US)
Pages (from-to)2430-2442
Number of pages13
Issue number9
StatePublished - Sep 1 2011
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


Dive into the research topics of 'Acomprehensive functional characterization of BRCA2 variants associated with Fanconi anemia using mouse ES cell-based assay'. Together they form a unique fingerprint.

Cite this