OBJECTIVE: Thyroid cancer (TC) is the most common endocrine malignancy, with 90%-95% of the cases representing non-medullary thyroid cancer (NMTC). Familial cases account only for a few of all cases and the underlying genetic causes are still poorly understood. METHODS: We whole-genome sequenced affected and unaffected members of an Italian NMTC family and applied our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2) which prioritized 12 coding variants. We refined this selection using the VarSome American College of Medical Genetics and Genomics (ACMG) implementation, SNAP2 predictions and further in silico scores. RESULTS: We prioritized 4 possibly pathogenic variants in 4 genes including Ret proto-oncogene (RET), polypeptide N-acetylgalactosaminyltransferase 10 (GALNT10), ubinuclein-1 (UBN1), and prostaglandin I2 receptor (PTGIR). The role of RET point mutations in medullary thyroid carcinoma is well established. Similarly, somatic rearrangements of RET are known in papillary TC, a specific histotype of NMTC. In contrast to RET, no germline variants in PTGIR, GALNT10, or UBN1 have been linked to the development of TC to date. However, alterations in these genes have been shown to affect pathways related to cell proliferation, apoptosis, growth, and differentiation, as well as posttranslational modification and gene regulation. A thorough review of the available literature together with computational evidence supported the interpretation of the 4 shortlisted variants as possibly disease-causing in this family. CONCLUSIONS: Our results implicate the first germline variant in RET in a family with NMTC as well as the first germline variants in PTGIR, GALNT10, and UBN1 in TC.

Biomedical Center Faculty of Medicine in Pilsen Charles University Prague Pilsen 32300 Czech Republic

Clinical Cooperation Unit Molecular Hematology Oncology German Cancer Research Center Heidelberg 69120 Germany

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases Heidelberg 69120 Germany

Department of Medicine 1 and Clinical Chemistry University Hospital of Heidelberg Heidelberg 69120 Germany

Division of Cancer Epidemiology German Cancer Research Center Heidelberg 69120 Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg 69120 Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg 69120 Germany

Heidelberg University Medical Faculty Heidelberg 69120 Germany

Hopp Children's Cancer Center Heidelberg 69120 Germany

IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna 40126 Italy

Unit of Medical Genetics Department of Medical and Surgical Sciences University of Bologna Bologna 40126 Italy

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