Abstract
Many genomic variants are currently classified, but many more are
extremely rare, have minimal associated patient data, and are classified
as variants uncertain significance (VUS). Accumulating patient data such
as family history and de novo status can help classify variants.
Understanding potential timelines for data accumulation and variant
classification can inform reporting, diagnosis, and treatment decisions.
We modeled future clinical data observations with different strategies
for sharing and aggregating clinical evidence for variants across
multiple sequencing centers over time. Models illustrate how long it
takes for variants to be classified when evidence is or is not shared
between clinical laboratories and compared to when only variant
interpretations are shared. When sequencing centers share evidence the
probability of classifying a one in 100,000 pathogenic variant increases
from less than 25% to nearly 80% after one year and to nearly 100%
with 5 years of observations. Extremely rare variants have a low
likelihood of classification using clinical data even with optimal data
sharing. Sharing clinical evidence between laboratories will lead to
faster and more certain classifications. Modeling can effectively
illustrate the likelihood of variant classification under current
classification frameworks and may help define realistic provider and
patient expectations.