Germline mutations predisposing to melanoma

J Cutan Pathol. 2020 Jul;47(7):606-616. doi: 10.1111/cup.13689. Epub 2020 May 11.


Nearly 15% of melanomas occur in patients with a family history and a subset of these patients have a germline mutation in a melanoma predisposing gene. CDKN2A mutations are responsible for the majority of hereditary melanoma, but many other susceptibility genes have been discovered in recent years, including CDK4, TERT, ACD, TERF2IP, POT1, MITF, MC1R, and BAP1. Additionally, melanoma risk is increased in mixed cancer syndromes caused by mutations in PTEN, BRCA2, BRCA1, RB1, and TP53. While early onset, multiple tumors, and family cancer history remain the most valuable clinical clues for hereditary melanoma, characteristic epithelioid cytology of melanocytic tumors may suggest an underlying BAP1 mutation. Herein, we review the clinical and histopathologic characteristics of melanocytic tumors associated with these germline mutations and discuss the role of genetic counseling.

Keywords: CDKN2A; germline mutation; hereditary; melanocytic nevus; melanoma.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Genes, p16
  • Genetic Predisposition to Disease
  • Germ-Line Mutation / genetics*
  • Humans
  • Melanoma / genetics*
  • Melanoma / pathology
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Middle Aged
  • Nevus, Pigmented / genetics*
  • Nevus, Pigmented / pathology
  • Phenotype
  • Receptor, Melanocortin, Type 1 / metabolism
  • Shelterin Complex
  • Telomerase / metabolism
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor Proteins / genetics
  • Ubiquitin Thiolesterase / genetics
  • Young Adult


  • ACD protein, human
  • BAP1 protein, human
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • MC1R protein, human
  • MITF protein, human
  • Microphthalmia-Associated Transcription Factor
  • POT1 protein, human
  • Receptor, Melanocortin, Type 1
  • Shelterin Complex
  • TERF2IP protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase 4
  • Telomerase
  • Ubiquitin Thiolesterase