A FANCC intronic variant of uncertain significance in a child with metastatic pancreatic adenocarcinoma

Abstract

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has been reported to have a germline genetic association in about 5.5% of isolated cases and 10–13% of familial or hereditary cohorts. Studies are linking new germline variants to PDAC annually, with numerous variants of uncertain significance (VUS) in candidate genes being reported. Case presentation: A 9-year-old boy presented with a 3-week history of abdominal pain, weight loss, and vomiting, with subsequent development of jaundice and pruritis. Imaging revealed an obstructive abnormality in the head of the pancreas with extra- and intrahepatic dilation of the bile ducts and a 1 c lesion in the liver. Biopsy of the liver lesion revealed metastatic PDAC. Extensive pathology review demonstrated atypical epithelial proliferation forming irregular and anastomosing glands. Germline evaluation was conducted with a 29-gene pancreatic cancer panel and revealed a c.345 + 6A > T VUS in the FANCC gene. This VUS affects a nucleotide in the consensus splice site in intron 4. The tumor was microsatellite stable with a tumor mutation burden of 3.4 Mutations/Mb. The child started chemotherapy with several cycles of FOLFIRINOX followed by Gemcitabine/Nab-paclitaxel but ultimately experienced tumor progression. He then pursued additional cancer directed therapy outside of our institution. As of the last evaluation, the child is alive with progressive disease. Conclusions Pancreatic adenocarcinoma is essentially unheard of in children under 10 years old. In adults, PDAC has been associated with a variety of cancer predisposition genes, and the National Comprehensive Cancer Network® (NCCN®) has issued surveillance guidelines for adults carrying germline variants in TP53, BRCA1/2, ATM, PALB2, CDKN2A, among others. Emerging data has identified germline FANCC variants in patients with PDAC. Further studies of FANCC variants of uncertain significance are necessary for variant reclassification and to allow review of current screening guidelines in adults.