Population prevalence of the major thyroid cancer-associated syndromes.

Understanding the population prevalence of thyroid cancer-associated syndromes is important to guide germline genetic testing and clinical management. To estimate the prevalence of the major thyroid cancer-associated syndromes in the United States using data from the All of Us Research Program (All of Us) and the UK Biobank. In this cross-sectional study, we identified pathogenic and likely pathogenic (P/LP) variants from the ClinVar database in 245,394 All of Us and 469,558, UK Biobank participants. We calculated the prevalence of thyroid cancer-associated syndromes defined by the presence of P/LP variants. Using logistic regression, we found that three hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, p = 3.23e-20), PTEN hamartoma syndrome (PHTS, PTEN gene, p = 2.59e-15), and familial adenomatous polyposis type 1 (FAP, APC gene, p = 2.73e-10) were significantly associated with thyroid cancer. The prevalence of thyroid cancer-associated syndromes in the All of Us was 1:2,172, 1:8,764, and 1:8,461, and in the UK Biobank, it was 1:2,348, 1:13,043, and 1:8,238 for MEN2, PHTS, and FAP, respectively. Three pathogenic RET variants that cause two amino acid substitutions, V804M and V804L, constitute 65% of all MEN2 variants in the All of Us, and none of these carriers were diagnosed with thyroid cancer. The prevalence of MEN2 and PHTS is ∼10-20 times higher than it is currently estimated for the general population. Most affected individuals are not diagnosed with thyroid cancer. Our findings may change the clinical approach to patients with moderate-risk RET mutations.