The research proposed here is in the area of cancer predisposition genetics, and its focus is on the moderate-
risk cancer susceptibility genes (ATM, CHEK2, etc.) in the biochemical pathway responsible for DNA double
strand break homologous recombination repair (HRR). Most of the genes in the HRR pathway are breast
cancer susceptibility genes, with several also being ovarian cancer susceptibility genes and/or pancreatic
cancer susceptibility genes. ¶ In the first funding cycle, we discovered that the majority of pathogenic alleles
in the moderate-risk HRR genes are individually rare missense substitutions (rather than the individually rare
protein truncating variants that dominate the mutation spectrum of BRCA1 and BRCA2). From a clinical
cancer genetics and patient counseling point of view, this observation creates a serious problem: the clinical
testing labs typically report these rare missense substitutions as Variants of Unclear Significance (VUS).
Because the VUS are not used for patient counseling, this means that the majority of the bona fide genetic risk
detectable in the moderate-risk HRR genes by the panel tests is not used for patient counseling and risk
management! ¶ Over the last 12 years, we played a central role in development of methods for clinical
classification of VUS in BRCA1 and BRCA2, and are currently developing corresponding methods for the
colorectal (and other cancer) susceptibility genes MLH1, MSH2, PMS2, and MSH6. Here, we hypothesize that
combining improved computational methods for rare missense substitution evaluation with comprehensive
high-throughput functional assays will dramatically accelerate the process of evaluation and classification of
clinically observed VUS. Thus the first Aim of the project focuses on confirming and then improving the
accuracy of computational methods for evaluation of rare missense substitution. The second Aim is directed
towards development of medium-to-high throughput assays of missense substitution functionality. In terms of
genes, we will begin these studies with the RING domain of BRCA1 (which lacks a properly calibrated
functional assay), and then progress to ATM and then CHEK2. In the third Aim, we re-calibrate the outputs
from the computational methods of Aim 1 and the functional assays of Aim 2 into probabilities (or odds) in favor
of pathogenicity, the key variables required for clinical-quality classification of sequence variants observed in
people. We then combine these data to obtain posterior probabilities in favor of pathogenicity and pass those
posterior probabilities through a well-recognized categorical classifier (the IARC standards) to generate
classification recommendations for clinicians and patients. Progress across the three Aims of this study will
dramatically accelerate variant classification while simultaneously improving the sensitivity and precision of the
clinical testing process.
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