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

Hirokazu Kimura, Raymond M. Paranal, Neha Nanda, Laura D. Wood, James R. Eshleman, Ralph H. Hruban, Michael G. Goggins, Alison P. Klein, Randall Brand, Michele L. Cote, Mengmeng Du, Steven Gallinger, Michael Goggins, Robert C. Kurtz, Gloria M. Petersen, Anil K. Rustgi, Ann G. Schwartz, Elena M. Stoffel, Sapna Syngal, George ZogopoulosNicholas J. Roberts

Research output: Contribution to journalArticlepeer-review


Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A 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 CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A 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 CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A 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.

Original languageEnglish (US)
Article numbere71137
StatePublished - Jan 2022

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology


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