Abstract
Disclosure: L.A. Ephraums: None. S.M. De Sousa: None. S. Stranks: None. L. Rawlings: None. H. Scott: None. C. Vakulin: None.
Background: Variants of uncertain significance (VUS) are genetic variants with inadequate evidence to be classified as pathogenic or benign (1). VUS results can cause anxiety, and failure to find a definitive causative variant precludes cascade testing of relatives. We present a case study of the value of MEN1 VUS reanalysis in individuals with clinical MEN1. Clinical Case: A 72-year-old man presented in 2016 for MEN1 genetic testing due to a history of primary hyperparathyroidism since age 45 (subsequent minimally invasive parathyroidectomy in 2022 consistent with parathyroid hyperplasia) and a family history in his mother of primary hyperparathyroidism and Zollinger-Ellison syndrome (histopathology unavailable). Genetic testing at SA Pathology in Adelaide, Australia, comprising an MEN1/CDKN1B next-generation sequencing gene panel, revealed a heterozygous variant in MEN1: c.135G>C, p.(Glu45Asp). With inadequate evidence from available resources to indicate pathogenicity or ‘benignity’, the variant was classified as a VUS. MEN1 surveillance investigations showed no other tumours. The patient was rereferred in 2024 with an incidentally detected pancreatic neuroendocrine tumour (NET). Drawing on our recent experience with VUS reanalysis in the endocrine gene setting (2), reanalysis was performed of the MEN1 VUS at SA Pathology. Now, with improved genetic resources compared to 2016 and use of the ACMG variant classification guidelines (1), the variant was reclassified as ‘likely pathogenic’ (i.e., positive). The ACMG pathogenicity criteria fulfilled were: variant reported in another affected patient (PS4_supporting), absence in population databases (PM2), other disease causing missense changes at this residue (PM5), deleterious computational predictions (PP3) and compatible phenotype (PP4). Reclassification of the MEN1 VUS to ‘likely pathogenic’ means that this patient now has a confirmed molecular diagnosis of MEN1, and this has facilitated cascade testing of his four children (results pending), including a son with suspected insulinoma. Conclusion: This case report illustrates the utility of periodic VUS reanalysis. This may be especially valuable in genetic endocrinopathies which have been traditionally less studied compared to other heritable conditions such as cancer and deafness, translating to a limited but growing evidence base to classify variants. References: 1.S Richards et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 20152.SMC 2. De Sousa et al. Improving detection of monogenic diabetes through reanalysis of GCK variants of uncertain significance. Acta Diabetol 2025
Presentation: Saturday, July 12, 2025