Classification of missense substitutions in the BRCA genes: a database dedicated to Ex-UVs

Hum Mutat. 2012 Jan;33(1):22-8. doi: 10.1002/humu.21629. Epub 2011 Nov 3.


Unclassified sequence variants (UVs) arising from clinical mutation screening of cancer susceptibility genes present a frustrating issue to clinical genetics services and the patients that they serve. We created an open-access database holding missense substitutions from the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. The main inclusion criterion is that each variant should have been assessed in a published work that used the Bayesian integrated evaluation of unclassified BRCA gene variants. Transfer of data on these substitutions from the original publications to our database afforded an opportunity to analyze the missense substitutions under a single model and to remove inconsistencies that arose during the evolution of the integrated evaluation over the last decade. This analysis also afforded the opportunity to reclassify these missense substitutions according to the recently published IARC 5-Class system. From an initial set of 248 missense substitutions, 31 were set aside due to nonnegligible probability to interfere with splicing. Of the remaining substitutions, 28 fell into one of the two pathogenic classes (IARC Class 4 or 5), 174 fell into one of the two nonpathogenic classes (IARC Class 1 or 2), and 15 remain in IARC Class 3, "Uncertain." The database is available at

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bayes Theorem
  • Breast Neoplasms / diagnosis*
  • Breast Neoplasms / genetics
  • Data Interpretation, Statistical
  • Databases, Genetic*
  • Exons
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genetic Variation
  • Humans
  • Middle Aged
  • Models, Statistical
  • Mutation, Missense*
  • Ovarian Neoplasms / diagnosis*
  • Ovarian Neoplasms / genetics
  • Prognosis
  • RNA Splicing
  • Risk Factors
  • Uncertainty