Prevalence of the major thyroid cancer-associated syndromes in the United States.

Importance: A subset of thyroid cancers develops in a setting of a known hereditary cancer-associated syndrome. Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management. Objective: To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using the All of Us Research Program (AoU) data. Design: In this cohort study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245,394 AoU biobank participants. We performed a logistic regression analysis of the association of ClinVar P/LP variants with thyroid cancer. P/LP variants in the genes of interest were manually curated to ensure match and pathogenicity status. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants. Results: Using logistic regression, we found that three hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, Conclusions and Relevance: The prevalence of MEN2 and PHPS is ~10-20 times higher than it is currently estimated for the general population (1:35,000 - 1,50,000 for MEN2 and 1:200,000-1:250,000 for PHTS). Most affected individuals are not diagnosed with thyroid cancer. These results further refine our understanding of the prevalence of hereditary syndromic thyroid cancers and may change the clinical approach to patients with moderate-risk