Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level

Area of Science:

• Clinical Genetics
• Molecular Diagnostics
• Bioinformatics

Background:

• Genetic testing frequently identifies variants of uncertain significance (VUS), causing patient and caregiver uncertainty.
• VUS can have varying degrees of evidence supporting pathogenicity or benignity, impacting clinical interpretation.

Purpose of the Study:

• To explore the subclassificaton of VUS by four clinical laboratories.
• To examine how VUS subclasses are utilized in laboratory investigations and reporting.
• To assess the reclassification trends of variants within these subclasses.

Main Methods:

• Analysis of VUS subclass composition across four distinct clinical laboratory approaches.
• Evaluation of the likelihood of variant reclassification (pathogenic or benign) from each subclass.
• Comparison of laboratory-specific methodologies for VUS subclass application.

Main Results:

• Laboratories employ diverse strategies for subclassifying and reporting VUS.
• VUS subclasses show varying probabilities of reclassification, indicating differential evidence for pathogenicity or benignity.
• Subclassification aids in prioritizing follow-up investigations and potentially influences medical decision-making.

Conclusions:

• Experience with VUS subclassificaton provides valuable insights for future practices.
• Anticipated professional guidance will recommend VUS subclass usage.
• Standardizing VUS subclass interpretation can enhance clinical utility and reduce diagnostic uncertainty.