Pathogenic CDKN2A germline variants are rare in a cohort of unselected pancreatic cancer patients from Pakistan.

Pancreatic cancer is a highly aggressive malignancy, with 10%-20% of cases linked to inherited genetic risk factors. Pathogenic variants (PVs) in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene have been associated with pancreatic cancer among Caucasians. However, data from South Asians are lacking. We investigated the prevalence of CDKN2A germline variants in 200 consecutively and prospectively enrolled, unselected pancreatic cancer patients from Pakistan. Comprehensive variant detection was performed using high-resolution melting analyses followed by DNA sequencing. Novel variants were investigated for pathogenicity using in-silico tools, and potentially functional variants were screened in 200 healthy controls. Five unique CDKN2A variants were identified, including one novel synonymous variant c.285G > T (p.Val95Val), one missense variant c.442G > A (p.Ala148Thr), one intronic variant (c.150 + 32A > T), and two variants (c.*29G > C and c.*69C > T) in the 3' untranslated region. No PVs in CDKN2A were detected. All variants were classified as benign, except the novel synonymous variant (p.Val95Val), which was categorized as a variant of uncertain significance (VUS) based on in-silico protein function prediction scores (Revel 0.38; PhyloP 2.88). This variant was identified in a 61-year-old male patient of Punjabi ethnicity with Grade 2 periampullary ductal adenocarcinoma with lymphovascular invasion and was absent in 200 healthy controls. Our study showed that CDKN2A PVs are very rare among unselected Pakistani pancreatic cancer patients, suggesting a negligible contribution to inherited pancreatic cancer risk in this population.