Multiple endocrine neoplasia type 1 with MEN1 c.652C>T (p.Arg218Trp): variant reclassified to likely pathogenic

Multiple endocrine neoplasia type 1 (MEN1) syndrome is the most common inherited cause of familial primary hyperparathyroidism. Diagnosis can be clinical, with at least 2 MEN1-associated tumors, or with 1 tumor plus a family history, or through genetic testing. A 31-year-old woman presented with hypercalcemia due to primary hyperparathyroidism. A 4-dimensional computed tomography (4D CT) and ultrasonography (US) of neck revealed 1 right-sided and 1 left-sided lesion consistent with parathyroid adenomas. Given her young age and a maternal history of primary hyperparathyroidism genetic testing was pursued and identified an MEN1 (NM_130799.2): c.652C>T (p.Arg218Trp) variant, reported as a variant of uncertain significance (VUS) with conflicting interpretations across laboratories. This variant had conflicting interpretations of VUS or pathogenic among several genetic testing laboratories. Further evaluation revealed a pancreatic neuroendocrine tumor and a pituitary cyst, with otherwise normal hormonal testing. Genetic testing in the patient's mother identified the same MEN1 variant. The presence of a clinical MEN1 diagnosis and familial segregation in 2 affected individuals provides additional evidence supporting reclassification of this variant from VUS to likely pathogenic.