Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families

Hum Mutat. 2005 Nov;26(5):495. doi: 10.1002/humu.9379.


Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Data Interpretation, Statistical
  • Family Health
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genetic Variation*
  • Humans
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / genetics
  • RNA Splice Sites*
  • RNA, Messenger / metabolism
  • Risk Factors


  • RNA Splice Sites
  • RNA, Messenger