The shifting landscape of germline RET pathogenic variants with the introduction of panel testing

The discovery and distribution of germline RET pathogenic variants are evolving. Current 2015 American Thyroid Association guidelines recommend testing for all patients with sporadic medullary thyroid cancer or RET-positive family members. More recently, incidental findings of RET pathogenic variants have emerged from panel testing for nonmedullary thyroid cancer indications. This study aimed to clarify the changing landscape of RET pathogenic variant identification over the last decade.

This retrospective, cross-sectional study analyzed data from major genetic testing laboratories for patients tested for RET pathogenic variants after January 2015. Testing types included single-gene testing, targeted panels, and broad panel testing. Outcomes assessed included testing type distribution and incidence of RET pathogenic variants.

Of 802,682 patients tested, 20,264 (2.5%) underwent single-gene testing, 15,229 (1.9%) targeted panel testing, and 767,189 (95.6%) broad panel testing. Among 1,793 identified RET pathogenic variants, 53.5% were found via single-gene testing, 4.1% via targeted panel testing, and 42.3% via broad panel testing. The most common variants were V804M, C609Y, and K666N in single-gene testing; C634R and V804M in targeted panel testing; and V804M, K666N, and C609Y in broad panel testing. Notably, 246 individuals carried RET pathogenic variants not listed in the 2015 American Thyroid Association guidelines, including K666N, M918V, C618G, and C618Y.

RET pathogenic variants V804M, K666N, and C609Y were the most identified variants, particularly through broad panel testing, indicating increased incidental diagnosis of MEN2. The identification of previously unlisted variants underscores the need for dynamic guideline updates and ongoing curation to optimize clinical management of RET pathogenic variant carriers.