This phenomenon has been observed for other genes associated with endocrine tumors (e.g. the SDHA in paraganglioma and cadherin-related 23 in pituitary adenomas) in which rare germline heterozygous coding variants are overrepresented in cases relative to controls but are associated with apparent low-disease penetrance (39,45). Here, CDH23 is linked to malignant endocrine neoplasm.