INVITED AND SPECIAL SESSIONS
Thursday, October 27
11:00 AM-1:00 PM
Concurrent Invited Sessions II (26-32)
SESSION 29 - Classification of Mutations in Disease Genes: Making Sense of Missense
Hall 3
Co-Moderators: Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; and Walter W. Noll, Myriad Genetic Laboratories, Salt Lake City, UT
Genetic testing for heritable mutations in disease susceptibility genes has become part of clinical practice.
The sequence variants that are identified include known deleterious mutations, benign polymorphisms, and unclassified variants (UCVs). Because of their ambiguous meaning, UCVs pose serious challenges for patient counseling and management. The problem is large and growing, particularly for cancer susceptibility genes. For example, of the 3500 sequence variants recorded in the international Breast Cancer Information Core (BIC) database, half are UCVs, and this number is increasing by 5-10 variants a week. UCVs are detected in 12% of the U.S. population undergoing BRCA1/2 testing, and a comparable percentage is seen in testing genes associated with hereditary colon cancer. This session will address the challenges posed by UCVs. An expert panel will discuss (1) the magnitude of the problem in managing patients and families, (2) the evidence that can be used to classify UCVs (frequency in cases and control, family studies, co-occurrence with deleterious mutations, the nature and position of amino acid substitutions, amino acid conservation among species, functional analyses of splice site or missense variants), and (3) approaches to integrating these various lines of evidence into predictive classification models (e.g., Goldgar et al. AJHG 2004;75:535-544).
11:00 AM Clinical genetic testing for heritable cancer susceptibility: The problem of unclassified sequence variants. Kenneth Offit.
11:20 AM Genetic approaches to mutation classification. Douglas F. Easton, University of Cambridge, United Kingdom.
11:40 AM Classification of splice site and missense sequence variants by functional assays. Fergus J. Couch, Mayo Clinic College of Medicine, Rochester, MN.
12:00 NOON Interpreting missense variants in CDKN2A, MLH1 and other genes. Marc S. Greenblatt, University of Vermont, Burlington.
12:20 PM Integrated evaluation of DNA sequence variants: Putting it all together. David E. Goldgar, University of Utah, Salt Lake City.
12:40 PM Questions and discussion.
