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Is 'likely pathogenic' really 90% likely? Reclassification data in ClinVar.

Steven M Harrison^1,2, Heidi L Rehm^3,4,5

¹Medical & Population Genetics Program and Genomics Platform, Broad Institute of MIT and Harvard, Main Street, Cambridge, MA, 02142, USA. steven@broadinstitute.org.

Genome Medicine

|November 23, 2019

Summary

This summary is machine-generated.

Professional guidelines define likely pathogenic variants as 90% likely to cause disease. A 2016-2019 ClinVar analysis revealed that most likely pathogenic classifications were reclassified as pathogenic, indicating evolving clinical practice.

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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

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Area of Science:

Genetics
Bioinformatics
Clinical Genomics

Background:

Professional guidelines established a 90% probability threshold for 'likely pathogenic' genetic variant classifications in 2015.
The interpretation of genetic variants is crucial for diagnosing hereditary diseases and guiding treatment decisions.

Purpose of the Study:

To evaluate whether clinical practice aligns with the 2015 definition of 'likely pathogenic' variants.
To analyze trends in genetic variant classifications within the ClinVar database.

Main Methods:

Tracking ClinVar variant classifications from 2016 to 2019.
Analyzing reclassification rates of variants initially labeled as 'likely pathogenic'.
Categorizing reclassifications, including those to 'pathogenic' and 'variant of uncertain significance' (VUS).

Main Results:

Between 83.8% and 99.1% of 'likely pathogenic' classifications were reclassified to 'pathogenic' during the study period.
The exact percentage varied based on the inclusion of 'likely pathogenic' to VUS reclassifications and specific categorization methods.
This suggests a dynamic shift in variant interpretation over time.

Conclusions:

Clinical practice in classifying genetic variants has evolved since the 2015 guidelines.
A high proportion of initially 'likely pathogenic' variants are ultimately classified as 'pathogenic', reflecting increased certainty or revised interpretations.
Ongoing monitoring of variant classification databases like ClinVar is essential for understanding real-world application of genetic testing standards.