Reinterpretation, reclassification, and its downstream effects: challenges for clinical laboratory geneticists

Area of Science:

• Clinical Genetics
• Genomic Medicine
• Laboratory Science

Background:

• Next-generation sequencing has dramatically increased genomic data in clinical genetics.
• Evolving knowledge of genetic variants and hereditary diseases impacts past genetic testing results.
• Recontacting patients for updated genetic information is well-studied, but laboratory handling of changing data is not.

Purpose of the Study:

• To explore the perspectives of clinical laboratory geneticists on the reinterpretation of genetic variants.
• To identify challenges and inform future guidelines for managing evolving genetic information in a laboratory setting.

Main Methods:

• A 7-day online focus group discussion was conducted.
• Fifteen clinical laboratory geneticists from all nine Dutch diagnostic laboratories participated.

Main Results:

• Laboratories primarily reinterpret genetic variants reactively, not proactively.
• Opinions varied on the desirability and feasibility of active reinterpretation, considering patient autonomy and laboratory responsibilities.
• Practices for reporting reclassified variants, especially variants of uncertain significance (VUS), differed among geneticists.

Conclusions:

• Five key challenges for future laboratory guidelines were identified.
• These include the need for routine active reinterpretation, patient consent integration, defining clinical significance for communication, determining appropriate re-evaluation strategies (reinterpretation, reanalysis, new testing), and understanding the impact of reclassification perceptions on practice.