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

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 BRCA

SUBMITTER: Goldgar DE 

PROVIDER: S-EPMC1182042 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature