UC Irvine

This study investigated the factors that trigger and drive reclassification of DNA variants of uncertain significance (VUS) in genes associated with high and moderate breast cancer risk (HBRGs and MBRGs). We examined 617 VUS reclassifications in 15 genes associated with hereditary breast cancer predisposition performed by a single commercial laboratory from January 2014 to January 2018. Almost 81% of the VUS reclassifications were downgrades, i.e. a VUS reclassified to likely benign (VLB) or benign. However, for VUSs that were reclassified in HBRGs over the study period it was determined that every year the odds of upgrade, i.e. a VUS reclassified to likely pathogenic (VLP) or pathogenic, increased by 68%. These results are significant considering VUS reclassification to pathogenic or VLP can lead to significant medical management changes for patients. Additionally, reclassified variants in HBRGs were more likely to use several lines of evidence (de novo occurrences, computational data, and protein functional assays) more frequently than reclassified variants in MBRGs. There were significant differences seen in evidence used depending on the reclassification direction, i.e. upgrade or downgrade. Availability of new research or data triggered reclassification of VUSs more frequently in HBRGs, but periodic variant review triggered reclassification more frequently in MBRGs. On average variants in HBRGs were reclassified five months sooner than variants in MBRGS. The results of this study support previously published data regarding frequency and direction of VUS reclassification and shed new light on the triggers of and evidence used for variant reclassification in HBRGs and MBRGs.