FAMMM syndrome (Familial Atypical Multiple Mole-Melanoma) is an autosomal dominant hereditary polygenic disease characterized by multiple dysplastic nevi and melanomas emerging at a young age.

In 20 - 40 % of hereditary melanomas there is a germline mutation in an important tumor-suppresor gene CDKN2A (cyclin-dependent kinase inhibitor 2A with transcriptional variants p16/INK4a and p14/ARF located on the chromosome 9 in the region 9q21). At the same time, mutation in this gene is found in 0.2 - 2 % of sporadic melanomas. Approximately in 1 % of hereditary melanomas there is found a germline mutation in cyclin-dependent kinase encoded by CDK4 (cyclin-dependent kinase 4 mapped into the region 12q14.1).

These muations disrupt the regulation of the central pathway of the cell cycle. Remaining cca 60 % are alterations in unknown genes.

Mutations in the gene CDKN2A cause, in the European population, about 60 % lifetime risk of getting melanoma and, on an average, 53 times higher (30 - 70 times) risk than the general population. Mutation carriers, except for the risk of melanoma, may also have an increased risk of pancreatic cancer at 11 – 17 %. Some studies have reported a higher risk of breast cancer in mutation carriers.


Our laboratory performs mutation analysis of the entire coding region of the gene CDKN2A including exon-intron joints and intron mutations IVS2-105A/G together with mutation detection in exon 2 of the gene CDK4 using PCR and direct sequencing.

Material for examination is peripheral blood; 0.5 - 1 ml of peripheral blood collected in EDTA tubes which is necessary to store in the fridge at 2 - 8 °C until transport (max. 5 days), transport from the ambulance to our laboratory is provided by the laboratory.

Clinical sensitivity:

In patients with familial melanoma syndrome (FAMMM) germline mutations of the CDKN2A gene were found in about 25 - 40% (Miller and Mihm, 2006).

Sequence analysis of the coding exons and exon-intron connections detects about 90% of mutations in the CDKN2A and the exon 2 gene CDK4 contained in a publicly available version of the mutation database HGMD (The Human Gene Mutation Database).

MLPA (Multiple-Ligation Probe Amplification) mutational analysis of large-scale (amplification / deletion) and the aberrant methylation detects about 10% of alterations in the gene CDKN2A listed in a publicly available version of the mutation database HGMD.

Analytical sensitivity and specificity of the sequencing: 99%.


Mutations deep in the introns and regulatory sequences are not detected. Rare polymorphisms in the location of primers annealing and probes may cause a diagnostic error.

In the case of the analysis of somatic mutations by sequencing the mutations will not be detected, if the altered cell line is not represented by at least 20%.


  1. Bishop DT, Demenais F, Goldstein AM et al. Geographical variation in the penetrance of CDKN2A mutati on for melanoma. NCI 2002; 94(12): 894- 903.
  2. Soufir N, Lacapere JJ, Bertrand G et al. Germline mutations of the INK4a- ARF gene in patients with suspected genetic predisposition to melanoma. BJC 2004; 90: 503- 509.
  3. Goldstein AM, Chan M, Harland M et al. Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents. J Med Genet. 2007 Feb;44(2):99-106. Epub 2006 Aug 11.