HABP2 Mutation and Nonmedullary Thyroid Cancer

On the basis of a study involving a single large kindred with seemingly nonsyn- dromic familial nonmedullary thyroid cancer, Gara and coworkers provide various lines of evi- dence that the G534E variant of HABP2 confers susceptibility to familial papillary thyroid can- cer. The filtering criteria they used to identify this variant required an allele frequency of 1% or less in public databases for variant prioritization, the rationale being that common variants are un- likely causes of rare diseases.1 However, several sources currently show allele frequencies for HABP2 G534E that approach 4% among Euro- peans and European Americans (Table 1). These frequencies resemble the reported frequency among patients with papillary thyroid cancer in the TCGA database (4.7%). Moreover, as the authors note, HABP2 G534E has been clinically associated with an increased risk of venous thrombosis2 and carotid-artery stenosis,3 as well as protection against liver fibrosis.4 These associations are also reported in the Human Gene Mutation Database (www.hgmd .cf.ac.uk/ac/index.php) and ClinVar (www.ncbi .nlm.nih.gov/clinvar/). Have Gara et al. tested their kindred members to rule out the presence of these conditions as well as other conditions that are potentially related to HABP2 G534E?