Population Prevalence of the Major Thyroid Cancer-Associated Syndromes.

[CONTEXT] 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 data from the All of Us Research Program (All of Us) and the UK Biobank.

[METHODS] 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.

[RESULTS] Using logistic regression, we found that 3 hereditary syndromes, multiple endocrine neoplasia type 2 (MEN2, RET gene, P = 3.23e-20), PTEN hamartoma tumor 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 1:2172, 1:8764, and 1:8461, and in the UK Biobank, it was 1:2348, 1:13 043, and 1:8238 for MEN2, PHTS, and FAP, respectively. Three pathogenic RET variants that cause 2 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.

[CONCLUSION] The prevalence of MEN2 and PHTS is ∼10 to 20 times higher than 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.