The challenge of comprehensive and consistent sequence variant interpretation between clinical laboratories

Area of Science:

• Genetics
• Molecular Biology
• Bioinformatics

Background:

• Genetic testing has transitioned from specialized academic labs to broad commercial offerings.
• This shift necessitates evaluating variant interpretation consistency across different laboratory types.

Purpose of the Study:

• To compare the variant interpretation model of an academic laboratory with those of several commercial laboratories.
• To identify discrepancies in genetic variant interpretation between academic and commercial settings.

Main Methods:

• The Collagen Diagnostic Laboratory (CDL) analyzed 38 variant interpretations from an outside laboratory (OL) over 14 months.
• Discrepancies between OL and CDL interpretations were systematically assessed.

Main Results:

• Concordance was observed in only 29% of interpretations; 29% had moderate discrepancies, and 42% had significant discrepancies.
• Key factors contributing to discrepancies included lack of public data sharing, underutilization of allele frequency data, and insufficient consideration of protein structure/function.

Conclusions:

• Accurate sequence variant interpretation relies on robust functional data and comprehensive variant databases.
• Enhanced consistency in genetic variant interpretation necessitates improved clinical information sharing, mandatory variant submission to public resources, and inter-laboratory expert collaboration.