cDNA analysis demonstrates that the BRCA2 intronic variant IVS4-12del5 is a deleterious mutation Journal Article


Authors: Zhang, L.; Bacares, R.; Boyar, S.; Hudis, C.; Nafa, K.; Offit, K.
Article Title: cDNA analysis demonstrates that the BRCA2 intronic variant IVS4-12del5 is a deleterious mutation
Abstract: Mutation screening of the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare non-truncating sequence variants in the BRCA1 and BRCA2 genes is problematic because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Several studies have reported the biochemical analysis of BRCA2 variants, which disrupted the 5′ and 3′splicing consensus elements (the GU-AG rule). However, little has been done to look into the consequences of variants located outside the 5′ and 3′ consensus splice sites. cDNA analysis demonstrates that the BRCA2*IVS4-12del5 splice site variant results in the deletion of exon 5, and the gene putatively produces a truncated BRCA2 protein of 164 amino acids instead of 3418 with the incorporation of 22 out of frame amino acids. The pattern of breast, melanoma, and pancreatic cancers in the paternal kindred is consistent with autosomal dominant inheritance of a deleterious BRCA2 mutation. Analysis of a tumor specimen indicates loss of heterozygosity (LOH). Sequence alignment indicates the deleted region is well conserved across different species. These results support the conclusion that BRCA2 IVS4-12del5 is a deleterious mutation. This study will shed light on the reclassification of intronic variants that do not disrupt the 5′ and 3′ splice sites (the GU-AG rule). © 2009.
Keywords: adult; human tissue; aged; middle aged; gene mutation; gene sequence; exon; gene deletion; mutation; exons; case report; pancreas cancer; melanoma; breast cancer; genetic variability; intron; alleles; introns; brca2 protein; pedigree; molecular sequence data; messenger rna; rna, messenger; sequence alignment; alternative splicing; base sequence; heterozygosity loss; cancer tissue; dna mutational analysis; loss of heterozygosity; brca2; dna determination; complementary dna; rna transcription; chromosome segregation; mrna; dna, complementary; splice mutation; autosomal dominant inheritance; dna splicing; pedigree analysis; segregation analysis
Journal Title: Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis
Volume: 663
Issue: 1-2
ISSN: 0027-5107
Publisher: Elsevier Science, Inc.  
Date Published: 2009-04-26
Start Page: 84
End Page: 89
Language: English
DOI: 10.1016/j.mrfmmm.2008.11.010
PUBMED: 19070627
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: MRFME" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Kenneth Offit
    509 Offit
  2. Clifford Hudis
    840 Hudis
  3. Khedoudja Nafa
    181 Nafa
  4. Liying Zhang
    88 Zhang
  5. Ruben Bacares
    15 Bacares
  6. Sherry R Boyar
    4 Boyar