Genetic variants of unknown significance (VUS) are differences in DNA sequences that are not clearly associated with a disease. They’re especially common in non-European populations because samples from people of European descent predominate in genomic databases—an overrepresentation that makes it difficult for clinicians to determine whether VUS might be pathogenic.

Findings published online on March 6 in Pediatrics by Daniel Weiser, M.D., and colleagues, including multiple Montefiore Einstein trainees, discuss how in-depth evaluation of several VUS enabled them to diagnose rare cancers in a diverse population of Bronx patients. In a case involving a 10-year-old Black girl, a VUS was reclassified as a likely contributor to von Hippel-Lindau disease, a condition leading to benign and malignant tumors throughout the body. The finding led to the detection and removal of an adrenal gland tumor from the girl a year later. 

Dr. Weiser is an associate professor of pediatrics and of genetics at Einstein and medical director of the Abdominal Solid Tumor Program at the Children’s Hospital at Montefiore Einstein. Corresponding author David Loeb, M.D., Ph.D., is professor of pediatrics and of developmental & molecular biology and the Linda and Earle Altman Faculty Scholar in Cancer Research at Einstein, as well as chief of pediatric hematology, oncology, and cellular therapy at the Children’s Hospital at Montefiore Einstein. Drs. Weiser and Loeb are members of the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center