Mutation screening of the breast and ovarian cancer-predisposition genes BRCA1 and
BRCA2 is becoming an increasingly important part of clinical practice. Classification
of rare nontruncating sequence variants in these genes is problematic, because it
is not known whether these subtle changes alter function sufficiently to predispose
cells to cancer development. Using data from the Myriad Genetic Laboratories database
of nearly 70,000 full-sequence tests, we assessed the clinical significance of 1,433
sequence variants of unknown significance (VUSs) in the BRCA genes. Three independent
measures were employed in the assessment: co-occurrence in trans of a VUS with known
deleterious mutations; detailed analysis, by logistic regression, of personal and
family history of cancer in VUS-carrying probands; and, in a subset of probands, an
analysis of cosegregation with disease in pedigrees. For each of these factors, a
likelihood ratio was computed under the hypothesis that the VUSs were equivalent to
an "average" deleterious mutation, compared with neutral, with respect to risk. The
likelihood ratios derived from each component were combined to provide an overall
assessment for each VUS. A total of 133 VUSs had odds of at least 100 : 1 in favor
of neutrality with respect to risk, whereas 43 had odds of at least 20 : 1 in favor
of being deleterious. VUSs with evidence in favor of causality were those that were
predicted to affect splicing, fell at positions that are highly conserved among BRCA
orthologs, and were more likely to be located in specific domains of the proteins.
In addition to their utility for improved genetics counseling of patients and their
families, the global assessment reported here will be invaluable for validation of
functional assays, structural models, and in silico analyses.