A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families

Am J Hum Genet. 2000 Aug;67(2):311-9. doi: 10.1086/303001. Epub 2000 Jun 22.


Germline mutations within the coding region of CDKN2A have been observed in affected members of melanoma-prone families. G101W is the most common CDKN2A missense mutation identified to date. It has been reported in several families from around the world, with a particularly high occurrence in France and Italy. Given the frequency of this mutation, we were interested in determining whether the mutation resulted from a single origin or represented a mutational hotspot in the CDKN2A gene. In addition, given the geographical distribution of the mutation, we examined the date of origination of the mutation and its migratory spread. We examined 10 families from Italy, 4 families from the United States, and 6 families from France with the G101W mutation. The following eight markers were employed for the haplotype analysis: IFNA, D9S736, D9S1749, D9S942, D9S1748, D9S1604, D9S171, and D9S126. Our findings showed no significant evidence for mutational heterogeneity, suggesting that all studied families derived from a single ancestral haplotype on which the mutation arose. Using maximum-likelihood methods, we estimated the mutation to have arisen 97 generations ago (1-LOD-unit support interval 70-133 generations) providing some explanation for the wide geographical spread of this common mutation, particularly in southwestern Europe. The presence of a founder mutation in a defined geographic area can facilitate carrier detection and genetic counseling and can provide an opportunity to study disease penetrance and the effect of environmental factors on the background of a common genetic susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Female
  • Founder Effect*
  • France
  • Gene Frequency / genetics
  • Genetic Heterogeneity
  • Genetic Markers / genetics
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Germ-Line Mutation / genetics*
  • Haplotypes / genetics
  • Humans
  • Italy
  • Likelihood Functions
  • Male
  • Melanoma / genetics*
  • Pedigree
  • Time Factors
  • United States


  • Cyclin-Dependent Kinase Inhibitor p16
  • Genetic Markers