FDA Recognizes PTEN Variant Criteria


Recently, for the first time, the FDA formally recognized the process that led to curation of a public database containing information about genes, gene variants and their relationship to disease as a source of valid scientific evidence that can be used to support clinical validity in premarket submissions. Among the gene variants listed in this database are variants of PTEN, a highly penetrant cancer susceptibility gene.

The Database

Known as ClinVar, the database was funded by the National Institutes of Health and curated by teams of more than 700 genetics experts who make up the Clinical Genome Resource (ClinGen) consortium. The ClinGen consortium’s work encourages sharing expertly curated and interpreted data on genetic variants, permitting developers to point to the genetic information available in the database to support the clinical validity of their tests, rather than gathering their own data, thus saving time and money.

Prior to this advancement, data about genetic variants were not always accessible, or were widely accessible but without uniform curation. A genetic database is a collection of research-generated information about genetic differences that, once organized, documents the evidence supporting links between a human genetic variant and a particular disease or condition. This information can be useful to researchers and developers, reducing regulatory hurdles in test development and spurring advancements in precision medicine. ClinVar differs from other databases because it is curated by experts from multiple institutions using systematic review procedures, is open to the public, and the FDA considers it a source of scientific evidence. This curation process is the first that is FDA approved.

Developing PTEN-Specific Criteria for the ClinVar Database

For some genes or disorders, expert variant curation groups already existed; however, for other genes, such as PTEN, expert panels had not yet been formed. In order to develop specifications to the Sequence Variant Interpretations Guidelines set forth in 2015 by the American College of Medical Genetics and the Association for Molecular Pathology for PTEN variants, a ClinGen PTEN Expert Panel was formed. Charis Eng, MD, PhD, founding chair of Cleveland Clinic’s Genomic Medicine Institute, co-chaired the panel.

In a recent article, the ClinGen PTEN Expert Panel described the finalized criteria for PTEN-specific variant classification and the outcomes of applying the criteria to a pilot group of 42 variants with benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS) and conflicting (CONF) ClinGen assertions. Applying the PTEN Exert Panel criteria to the BEN/LBEN and PATH/LPATH led to an overall concordance of 96.8%. When applying these rules to six VUS and two CONF variants, with some additional data from a shared internal library, one VUS was reclassified as LBEN and two CONF variants were reclassified as PATH and LPATH.

One of PTEN's roles in the body is as a tumor suppressor gene, which means that when it works correctly, PTEN helps slow or prevent growth of pro-cancer cells that may develop into tumors. Receiving a result of VUS or CONF can present clinical challenges, as genetic findings are often used in surgical decision-making and to determine a patient’s cancer surveillance protocol. Dr. Eng states, “FDA recognition of the PTEN Expert Panel’s assertions means that cancers may be found earlier, and perhaps even prevented, in some patients.”