Researchers from the US modified the 2015 guidelines of the American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP) specifically for multiple endocrine neoplasia type 2 (MEN2) syndromes, like medullary thyroid carcinoma (MTC), and RET variants, according to a recent study.

The update “will optimize and standardize RET variant classifications,” the authors said.

The team, led by Rong Mao, MD, FACMG, codirector of the Laboratory Genetics and Genomics Fellowship, University of Utah School of Medicine in Salt Lake City, used manuscripts from the American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma and the recommendations of the ClinGen sequence variant interpretation working group and ClinGen expert panel manuscripts to modify the guidelines.  

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The study is published in the journal Human Mutation, Variation, Informatics, and Disease.

The researchers analyzed the classifications for the 166 single unique variants in the MEN2 RET database. They created 2 new variant classifications in the database: “likely benign” and “likely pathogenic.”

The analysis also led to clinically significant classification changes in 15.7% of the original variants. For example, certain variants changed from “pathogenic” to “uncertain,” while others changed from “uncertain” to “benign” or “likely benign.”

The new variant reclassification “has led to a more updated and precise resource for clinicians and researchers,” the authors noted.

Medullary thyroid carcinoma is a rare type of tumor of the thyroid gland arising from the parafollicular cells. Although most cases are sporadic, 25% of cases have a hereditary origin as part of the MEN2 syndromes. Moreover, 40% to 50% of sporadic cases have acquired RET mutations in the neural crest tissue.

RET codes for a transmembrane receptor of the tyrosine kinase family. Mutations in the RET gene drive the continuous phosphorylation of tyrosine residues, thereby activating signaling pathways inside cells, which play a role in cell survival, differentiation, and proliferation.


Margraf RL, Alexander RZ, Fulmer ML, Miller CE, Coupal E, Mao R. Multiple endocrine neoplasia type 2 (MEN2) and RET specific modifications of the ACMG/AMP variant classification guidelines and impact on the MEN2 RET database. Hum Mut. Published online October 17, 2022. doi:10.1002/humu.24486