Integrated evaluation of DNA sequence variants of unknown clinical significance: Application to BRCA1 and BRCA2

David E. Goldgar, Douglas F. Easton, Amie M. Deffenbaugh, Alvaro N.A. Monteiro, Sean V. Tavtigian, Fergus J. Couch

Research output: Contribution to journalArticle

274 Scopus citations

Abstract

Many sequence variants in predisposition genes are of uncertain clinical significance, and classification of these variants into high- or low-risk categories is an important problem in clinical genetics. Classification of such variants can be performed by direct epidemiological observations, including cosegregation with disease in families and degree of family history of the disease, or by indirect measures, including amino acid conservation, severity of amino acid change, and evidence from functional assays. In this study, we have developed an approach to the synthesis of such evidence in a multifactorial likelihood-ratio model. We applied this model to the analysis of three unclassified variants in BRCA1 and three in BRCA2. The evidence strongly suggests that two variants (C1787S in BRCA1 and D2723H in BRCA2) are deleterious, three (R841W in BRCA1 and Y42C and P655R in BRCA2) are neutral, and one (R1699Q in BRCA1) remains of uncertain significance. These results provide a demonstration of the utility of the model.

Original languageEnglish (US)
Pages (from-to)535-544
Number of pages10
JournalAmerican journal of human genetics
Volume75
Issue number4
DOIs
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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