We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region. No other germline TP53 mutation was detected in these samples. Germline TP53 mutation, usually associated with Li-Fraumeni syndrome, is a rare event in UM. To the best of our knowledge, only one family with germline TP53 mutation has previously been described. In our study, we detected TP53 mutation in two patients without known family relationship. The identification of germline aberrations in TP53 or BAP1 is important to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome, which is also crucial for proper genetic counseling.

1st Department of Surgery Department of Abdominal Thoracic Surgery and Traumatology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Clinic of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

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A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants