Nobody Likes Uncertainty

By Marisa Vomvos, MS · Oct 2018

A New York Times article referenced a study by Myriad Genetics, published in JAMA, on reclassification of variants found in hereditary cancer testing in 1.45 million individuals over 10 years. It highlighted one of the most common and frustrating experiences in genetic testing: the variant of uncertain significance.

What Is a Variant of Uncertain Significance?

Genetic testing results use a 5-tier classification system: benign, likely benign, variant of uncertain significance (VUS), likely pathogenic, and pathogenic. A VUS is exactly what it sounds like — a variant in the DNA sequence whose pathogenicity is uncertain because there isn't enough data to know whether it's harmful or harmless. Medical intervention is generally not recommended in response to a VUS, meaning patients may wait years for reclassification.

What the Myriad Study Found

Among the approximately 25% of VUSs that were reclassified over 10 years, 91.2% were downgraded to benign or likely benign, while 8.5% were upgraded to pathogenic or likely pathogenic. Reclassification of clearly benign or clearly pathogenic variants was rare (0.2% and 0.7%, respectively). However, about 75% of VUSs were not reclassified during the entire study period.

What helps: labs developing more systematic reclassification processes, open-access databases like ClinVar, and large-scale research programs like NIH's All of Us that are working to expand the diversity of genomic reference databases — a critical gap, since most existing databases are most representative of European ancestry populations.