Excerpts from the article published in The American Journal of Human Genetics by Douglas M. Fowler and Heidi L. Rehm (https://www.cell.com/ajhg/fulltext/S0002-9297(23)00400-7) In the rapidly evolving field of genomic medicine, a key question remains on the horizon: will we still be grappling with Variants of Uncertain Significance (VUS) by 2030? In 2020, the National Human Genome Research Institute (NHGRI) made a bold prediction: by 2030, the clinical relevance of all genomic variants would be readily predictable, making the classification of VUS obsolete. Despite the optimism, the number of VUS submissions in global genomic databases like ClinVar has only continued to grow. But as we near the decade’s close, there is cautious optimism that the prediction may yet come true. What Are Variants of Uncertain Significance (VUS)? When a genetic test is conducted, the results often include variants—differences in DNA that may be linked to disease. However, not all variants are well understood. A VUS is a genetic variant for which there is not enough information to classify it as either pathogenic (disease-causing) or benign (not harmful). This uncertainty creates challenges for clinicians trying to interpret genetic test results and develop treatment plans. The high prevalence of VUS—currently estimated at around 36% of submissions in ClinVar—reflects the difficulty in connecting genetic variation to clinical outcomes. For patients receiving a VUS result, this often represents a diagnostic “dead end,” leaving them without answers regarding their condition. Why Is Eliminating VUS So Important? In clinical practice, a VUS result can significantly hinder the ability of doctors to guide treatment or predict disease risk. Even though VUS results do not indicate immediate danger, they complicate the patient’s diagnostic journey. The rise in genetic testing has led to a surge in VUS reports, making it increasingly critical to resolve these variants and ensure that genetic insight