Rates and classification of variants of uncertain significance in hereditary disease genetic testing

Many cancer patients and their family members are encouraged to undergo germline genomic testing to evaluate the risk for cancer among their family members. Genomic sequencing has identified many rare, novel DNA variants in diverse populations. To determine whether a variant is associated with disease, laboratory geneticists follow guidelines for classifying variants as pathogenic or likely pathogenic that can help physicians confirm diagnoses, provide prognoses, refine treatment strategies, and address risks for family members. However, many of the variants detected are classified as variants of uncertain significance (called “VUS”) because available evidence at the time of their discovery is not sufficient to establish their involvement in disease. VUSs can be reassessed when additional evidence emerges, sometimes leading to reclassification as being either pathogenic or likely pathogenic or benign or likely benign.

VUSs frustrate physicians and patients and can be misinterpreted. Physicians are sometimes uncomfortable counseling patients about VUSs, and some patients experience long-term anxiety. Furthermore, VUSs are more frequent among Asian, Black, and Hispanic individuals, adding to the existing health disparities affecting these populations, which is due in part to their underrepresentation in genomics studies.

This multi-institutional, multi- national study of more than 1.6 million individuals used germline DNA variant data from individuals referred by clinicians for diagnostic genetic testing for hereditary disorders. The study population included Ashkenazi Jewish, Asian, Black, French Canadian, Hispanic, Native American, Pacific Islander, Sephardic Jewish, and White individuals.

Among all individuals tested, 41.0% had at least 1 VUS and 31.7% had only VUS results. Most (86.6%) of the VUSs were in so-called DNA missense changes that change the coding of protein structure, some of which alter the function of the resulting protein. More VUSs were observed in the non-White populations. Of unique VUSs that were reclassified, 80.2% were ultimately categorized as benign or likely benign.

On average, 31 months elapsed for VUSs to be reclassified to benign or likely benign, and 22.4 months elapsed for VUSs to be reclassified to pathogenic or likely pathogenic.

This study highlights the need for better methods for interpreting missense variants, more clinical and experimental evidence for variant classification, and a more diverse representation of ethnicity groups in genomic studies.

Chen E, et al. JAMA Netw Open. 2023;6(10):e2339571. Published 2023 Oct 2. doi:10.1001/jamanetworkopen.2023.39571