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ClinGen TP53 Variant Curation Expert Panel Guidelines Finalized

, by DCEG Staff

Sharon Savage, Megan Frone, Kelvin de Andrade, and Jessica Hatton participated in ClinGen TP53 Variant Curation Expert Panel.

From left to right: Sharon Savage, Megan Frone; Kelvin de Andrade, Jessica Hatton

New classification guidelines for germline variants of the tumor suppressor gene TP53 were published online in Human Mutation in March 2021. Inherited variants in TP53 are the cause of the cancer predisposition syndrome known as Li-Fraumeni Syndrome (LFS).

The rule specifications, developed by the ClinGen TP53 Variant Curation Expert Panel (VCEP), follow the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for germline variant classification. The updated TP53-specific classification guidelines provide critical information for the health care providers engaged in clinical management of LFS patients as well as those who receive genetic testing results that indicate an alteration in TP53 that may be benign. The TP53‐specific guidelines and sharing of clinical data among experts and clinical laboratories reduced clinically-relevant discrepancies and led to a decrease in reporting of variants of uncertain significance from 28% to 12%, compared with the original guidelines. Additionally, the new guidelines will inform the direction of biomedical research studies into the biologic function of such variants. 

The ClinGen TP53 VCEP is chaired by Sharon A. Savage, M.D., chief of the Clinical Genetics Branch (CGB). Several other CGB experts participated in the panel: Megan Frone, M.S., C.G.C., genetic counselor, serves as panel coordinator and heads variant biocuration, and postdoctoral fellow Kelvin de Andrade, Ph.D., and genetic counselor Jessica Hatton, M.S., C.G.C., serve as biocurators. The NCI Li-Fraumeni Screening Study, a rich database representing one of the largest cohorts of LFS patients in the world, was a valuable source of internal data utilized both for VCEP rule development as well as for individual variant curation. ClinGen, an ongoing initiative supported by the National Human Genome Research Institute, part of the National Institutes of Health (NIH), is the first and only process and database recognized by the U.S. Food and Drug Administration for human genetic variant interpretation.

The TP53 panel is one of more than 30 such groups working towards evidence-based, consistent germline variant interpretation, combining scientific and clinical expertise to adapt the ACMG-AMP variant interpretation guidelines to a specific gene. The TP53 VCEP began the FDA-approved process for rule modifications in October 2015 and was approved in August 2019. The VCEP submitted its first batch of variants to the ClinVar database in January 2020. Currently, over 130 TP53 variants have been finalized and are in various stages of submission to the ClinVar variant database, a publicly available resource funded by National Center for Biotechnology Information at the NIH National Library of Medicine. 

The ability to accurately classify variants for established oncogenes is possible because of the involvement and data sharing of DCEG and many other research groups on assembling well-annotated study populations with excellent pedigree information and high-quality laboratory testing and follow-up functional studies of new variants. The BRCA Challenge, spearheaded by Stephen J. Chanock, M.D., was the first such effort, completed in 2019, yielding a comprehensive—and growing—global database of thousands of variants in BRCA1 and BRCA2. CGB Medical Geneticist and senior investigator Douglas Stewart, M.D., serves as co-chair of the VCEP for DICER1 and miRNA Processing Genes, and leads the ClinGen Hereditary Cancer Working Group. Ms. Hatton and Cecilia Higgs are co-coordinators; Jung Kim, Ph.D., research fellow, is a member of the panel and Ms. Frone is a panel member and provides biocuration. The group formed in July 2019 and completed a draft of DICER1 rule specifications in November 2020; they are piloting their rules for refinement before final publication.