Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models

Curr Opin Genet Dev. 2010 Jun;20(3):315-23. doi: 10.1016/j.gde.2010.03.009. Epub 2010 Apr 22.

Abstract

Multifactorial models developed for BRCA1/2 variant classification have proved very useful for delineating BRCA1/2 variants associated with very high risk of cancer, or with little clinical significance. Recent linkage of this quantitative assessment of risk to clinical management guidelines has provided a basis to standardize variant reporting, variant classification and management of families with such variants, and can theoretically be applied to any disease gene. As proof of principle, the multifactorial approach already shows great promise for application to the evaluation of mismatch repair gene variants identified in families with suspected Lynch syndrome. However there is need to be cautious of the noted limitations and caveats of the current model, some of which may be exacerbated by differences in ascertainment and biological pathways to disease for different cancer syndromes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation
  • Germ-Line Mutation*
  • Humans
  • Models, Genetic
  • Neoplasms / genetics*
  • Risk Factors

Substances

  • BRCA1 Protein
  • BRCA2 Protein