Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

• Published in: eLife Vol. 11
• Main Authors: Kimura, Hirokazu, Paranal, Raymond M, Nanda, Neha, Wood, Laura D, Eshleman, James R, Hruban, Ralph H, Goggins, Michael G, Klein, Alison P, Roberts, Nicholas J
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 10.01.2022; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adenocarcinoma; Alleles; cancer; Cancer Biology; Carcinoma, Pancreatic Ductal - genetics; CDKN2A; Cell cycle; Cell growth; Cell proliferation; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; familial cancer; Family medical history; Genetic aspects; Genetics; Genetics and Genomics; Germ-Line Mutation; Health aspects; Hruban, Ralph H; Humans; pancreas; Pancreatic cancer; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Patients; variant of uncertain significance; genetics; familial cancer; CDKN2A; pancreas; variant of uncertain significance; genomics; cancer; cancer biology; human; pancreatic ductal adenocarcinoma
• DOI: 10.7554/eLife.71137
• ISSN: 2050-084X

Pathogenic germline variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of VUSs is needed to reclassify variants and inform clinical management. Twenty-nine germline VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve of the 29 VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.