Letter to the Editor: “A Unique Case of Metastatic, Functional, Hereditary Paraganglioma Associated With an SDHC Germline Mutation”

Several recently published articles (1–5) in Journal of Clinical Endocrinology & Metabolism report variant interpretation using terms that are no longer encouraged by the standards and guidelines as outlined by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (6). Terms such as “mutation” and “polymorphism” that refer to a permanent change in the nucleotide sequence and a variant with a frequency >1% in the general population, respectively, lead to confusion because of incorrect assumptions of pathogenic and benign effects (6). Thus, in 2015, standards and guidelines for the interpretation of sequence variants were created using a five-tier system of classification to design a framework with universal applicability. The term “variant” was preferred to mutation and polymorphism. Variants are further classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign (6).

These guidelines have been adopted by many US and international laboratories and journals, requiring substantial expertise to be applied correctly for specific diseases and genes. The fluidity of this classification system allows for reclassification of variants (e.g., from VUS to benign) as new or updated reports with multiple new cases or families, including functional laboratory studies, are released. A recent study that examined hereditary cancer genetic results from >1.5 million individuals using a single-gene or small panel test showed that ∼24.9% of VUSs were reclassified, which included both downgrades and upgrades (7). Thus, we encourage the adoption of this framework by all endocrine journals to assist in the standardization of variant interpretation practices across all Mendelian disorders.

Glossary

Abbreviation:

VUS

variant of uncertain significance.