Grant: CIHR Fellowship

Clinical genetic testing can generate complex results, including variants of uncertain significance (VUS). These are genetic variants whose clinical significance cannot be interpreted due to insufficient or conflicting evidence about their role in disease. These results are challenging for diagnostic laboratories, clinicians, and patients to manage. New guidelines for interpreting genetic sequence variants will include VUS "sub-tiers," allowing laboratories to differentiate between those that are more likely to be disease-causing, and those that are more likely to be benign. It is unknown how these new guidelines will impact laboratory practice, and how these VUS sub-tiers will be interpreted by patients and healthcare professionals. This study aims to to 1) characterize VUS sub-tiers and variant reclassifications across laboratories, and 2) explore patient and HCP experiences with reports containing VUS. To address Aim 1, data from clinical diagnostic laboratories will be aggregated and analyzed to assess the frequency of VUS across sub-tiers, laboratory concordance in sub-tier classifications, and rate and direction of variant reclassifications. To address Aim 2, qualitative interviews will be conducted with patients and healthcare professionals who have received test reports with VUS sub-tiers, to explore experiences with VUS sub-tiers, and views toward VUS sub-tiers and laboratory reporting of VUS. VUS are an issue of growing importance as genomic tests are increasingly used across medical specialties and in population-scale sequencing initiatives. This project will generate evidence to inform practice standards for diagnostic laboratories, providing guidance on reporting VUS to optimize clinical utility and mitigate patient harm.