CM-Score: A validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe

Research output: Contribution to journalArticle


Background: Several factors have been reported that influence the probability of a germline CDKN2A mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. Methods: Five clinical features and their association with CDKN2A mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (CDKN2A Mutation(CM)-Score) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with CDKN2A mutation). Results: All five features were significantly associated (p<0.05) with a CDKN2A mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). Conclusion: We developed a practical scoring system to predict CDKN2A mutation status among melanoma-prone families. We suggest that CDKN2A analysis should be recommended to families with a CM-Score of ≥16 points.


  • Thomas P. Potjer
  • Hildur Helgadottir
  • Mirjam Leenheer
  • Nienke Van Der Stoep
  • Nelleke A. Gruis
  • Veronica Höiom
  • Håkan Olsson
  • Remco Van Doorn
  • Hans F.A. Vasen
  • Christi J. Van Asperen
  • Olaf M. Dekkers
  • Frederik J. Hes
External organisations
  • Leiden University Medical Centre
  • Karolinska University Hospital
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cancer and Oncology


  • cancer: dermatological, cancer: head and neck, clinical genetics, genetic epidemiology, genetic screening/counselling
Original languageEnglish
Pages (from-to)661-668
JournalJournal of Medical Genetics
Issue number10
Early online date2018 Apr 16
Publication statusPublished - 2018
Publication categoryResearch