CDKN2A

Gene Facts

• HGNC Symbol: CDKN2A (HGNC:1787)
• HGNC Name: cyclin dependent kinase inhibitor 2A
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: CDKN2, MLM
• Alias symbols: CDK4I, p16, INK4a, MTS1, CMM2, ARF, p19, p14, INK4, p16INK4a, p19Arf, p14ARF, P16-INK4A, CAI2
• %HI: 0.81
• pLI: 0.62
• LOEUF: 0.79
• Cytoband: 9p21.3
• Genomic Coordinates:

  GRCh37/hg19:	chr9:21967751-21995323
  GRCh38/hg38:	chr9:21967752-21995324

• MANE Select Transcript: NM_000077.5 ENST00000304494.10
• MANE Plus Clinical Transcript(s):

  NM_058195.4 ENST00000579755.2 (Read more about MANE Plus Clinical)

• Function: Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein. {ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:7972006}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-12408
• ClinGen Curation ID: CCID:006830
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  PMID: 12789280. NK Hayward (2003) reviewed the genes predisposing to melanoma. CDKN2A is one of the well-established high penetrance genes. PMID: 17196510. Bishop et al (2007) reviewed the evidence that the increasing risk of melanoma is attributed to both susceptibility genes and environment factors. CDKN2A is the gene with most frequent high-penetrance susceptibility to melanoma. PMID: 12072543. Bishop et al (2002). By age 80 years CDKN2A mutation penetrance was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia.
• Last Evaluated: 03/18/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• melonoma

HI Evidence

• PUBMED: 30291219
  Helgadottir et al., 2020. Four patients (patient ID 6, 12, 13, and 18) with melanoma had a germline deletion of 119 bp (c.225_243del119) in CDKN2A gene. They have received immunotherapy for metastatic melanoma.
• PUBMED: 29661971
  Potjer et al., 2018. Five clinical features and their association with CDKN2A variants were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A variants). A 155 kb deletion including the entire CDKN2A gene was identified in a patient with melanoma.
• PUBMED: 12072543
  Bishop et al., 2002. The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. By age 80 years CDKN2A mutation penetrance was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. A 24bp deletion (c.9_32del24 p.Ala4_Pro11del) in a patient with melanoma was detected. This deletion is located in exon1A of p14ARF protein isoform.
• PUBMED: 11156381
  Hashemi et al., 2000. They screened 80 individuals with at least two primary cutaneous melanomas, who were identified mainly by a search of a regional cancer registry, for germ-line CDKN2A variants. One patient, who also had a family history of melanoma, had a 24-bp deletion that included codons 62-69 (c.185_208del24 p.Leu62_Glu69del).
• PUBMED: 18612309
  Lesueur et al., 2008. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. They examined 214 patients from independent pedigrees with at least two cutaneous malignant melanoma (CMM) cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2 (2935 bp, c.150+1713_457+873del2937 p.Val51Thrfs*40). Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility.

• HI Evidence Comments: It is well known that germline mutations of CDKN2A are the most common cause of inherited susceptibility to melanoma. This gene has 2 clinically relevant transcripts which encode two different proteins isoforms (p16INK4A and p14ARF). PMID: 10861313 Goldstein et al., 2000 CDKN2A has been implicated in the development of cutaneous malignant melanoma (CMM). CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer. PMID: 22841127 Maubec et al., 2012 The frequency of CDKN2A mutations was higher (32%) in families with 3 or more patients with cutaneous melanoma (CM) than in families with 2 patients (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in families with 2 patients, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in families with 3 or more CM patients.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity