• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit



ARF; CDK4I; CDKN2; CMM2; INK4; INK4A; MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4; P16INK4A; P19; P19ARF; TP16

Associated disorders

The CDKN2A gene is associated with autosomal dominant hereditary melanoma-pancreatic cancer syndrome (MedGen UID: 325450) (OMIM: 600160).

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CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.

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Invitae tests that include this gene:

The gene CDKN2A is a tumor-suppressor gene. This gene generates several alternative transcripts that encode proteins that regulate cell cycle control genes p53 and RB1. Alternative transcripts of CDKN2A produce two major proteins: p14, which is a stabilizer of the tumor-suppressor protein p53, and p16, which regulates G1-phase exit by inhibiting the CDK4-mediated phosphorylation of the protein RB1.

CDKN2A heterozygotes
OMIM: 155601, 606719

Clinical condition
Approximately 5-12% of all melanoma diagnoses occur in individuals with a strong family history of melanoma (PMID: 28283772, 16192601), and 5-10% of pancreatic cancer is thought to occur due to hereditary risk (PMID: 17872573). The CDKN2A gene is associated with autosomal dominant melanoma-pancreatic cancer syndrome (PMID: 18178632, 26892650) and also with a rare, emerging syndrome called melanoma-neural system tumor (melanoma-NST) syndrome (PMID: 9622062, 19095153, 11433531, 26876133). The CDKN2A gene encodes two distinct proteins: p16INK4a and p14ARF.

Melanoma-pancreatic cancer syndrome is associated with inherited susceptibility to develop malignant melanoma, pancreatic cancer, and possibly other cancer types (Eckerle Mize D, Bishop M, Resse E, et al. Familial Atypical Multiple Mole Melanoma Syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al., editors. Cancer Syndromes [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2009. Available from: http://www.ncbi.nlm.nih.gov/books/NBK7030/, PMID: 26892650). Some families with CDKN2A variants include individuals with both melanoma and pancreatic cancer; however, some may present with only melanoma or pancreatic cancer (PMID: 21150883). Individuals with pathogenic CDKN2A variants may develop multiple primary melanomas (PMID: 25780468), and some studies have also reported a younger age at melanoma diagnosis (PMID: 25780468, 16896043). The term familial atypical mole-malignant melanoma syndrome (FAMMM) may be used to refer to individuals with melanoma-pancreatic cancer syndrome who also have multiple atypical nevi (PMID: 16905682, 25431349, 26892650).

The majority of pathogenic variants in CDKN2A impact only the p16INK4a protein; therefore the available data and cancer risks are primarily for individuals with CDKN2A variants affecting p16INK4a function. Depending on the study design and target population, the reported risk of CDKN2A-associated melanoma differs widely, ranging from 13% to 91% (PMID: 12072543, 16234564, 21150883, 26488006, 26892650, 18559569). The risk of melanoma in an individual with a pathogenic CDKN2A-p14ARF variant is also elevated, but the exact risk is unknown. The lifetime risk of pancreatic cancer in individuals with pathogenic CDKN2A-p16INK4a variants has been reported to range from 11-58% (PMID: 18559331, 21159883, 9622062, 10956390). There is currently no evidence supporting an association of pancreatic cancer among individuals with pathogenic CDKN2A-p14ARF variants; however, more studies are needed. There is evidence that there may be environmental and genetic modifiers influencing these cancer risks (PMID: 16462187, 12072543). For example, tobacco smoking has been associated with a significantly increased risk for pancreatic cancer (PMID: 24935963, 21150883).

Pathogenic variants in CDKN2A affecting the p14ARF protein have been implicated in melanoma-neural system tumor (melanoma-NST) syndrome (PMID: 19095153, 11433531, 26876133). This is a rare condition characterized by multiple melanocytic nevi and an increased lifetime risk of developing cutaneous melanoma and neural system tumors, including astrocytoma and nerve sheath tumors (PMID: 9622062, 11136714, 17047042, 20132244). Some of these individuals were initially misdiagnosed as having neurofibromatosis type 1 (NF1) (PMID: 9259954, 26876133).

Pathogenic variants or deletions that impact both the p16INK4a and p14ARF proteins have been reported among affected individuals, and appear to result in clinical features of both melanoma-pancreatic cancer and melanoma-NST syndromes and possibly an increased risk of developing other cancers (PMID: 11433531, 26876133).

Finally, there is emerging data to suggest that CDKN2A may be associated with sarcoma (PMID: 25704628), and therefore it is available as a “preliminary-evidence” gene on Invitae’s Sarcoma panel. Preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these limited evidence genes.

Gene information
CDKN2A is a tumor suppressor gene comprised of 4 exons (1a, 1b, 2, and 3) that encode two tumor suppressor proteins, p16 (1a, 2, and 3) and p14 (exons 1b, 2, and 3), via differential splicing and alternative reading frames (PMID: 26488006). p14 is a stabilizer of the tumor suppressor protein p53, and p16 promotes the arrest of the cell cycle in the G1 phase by inhibiting CDK4-mediated phosphorylation of the RB1 protein (PMID: 26488006, NCBI Gene. Gene ID: 1029. http://www.ncbi.nlm.nih.gov/gene/1029. Accessed May 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers can be increased.

Pathogenic variants in CDKN2A have autosomal dominant inheritance. This means that an individual with a pathogenic variant in CDKN2A has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but some cases can occur spontaneously (i.e., the parents of an individual with a pathogenic variant in CDKN2A do not have it).

Both malignant melanoma and pancreatic cancer can be difficult to treat and are associated with high mortality if not identified in early stages (PMID: 26892650, 28121081, 23135763). While there are no established screening guidelines for individuals with CDKN2A variants, the following recommendations have been suggested (PMID: 25431349, 26892650, 26488006):


  • Total body skin examination and dermoscopic examination of clinically atypical nevi with possible total body photography (TBP) and sequential digital dermoscopy imaging (SDDI)
    • Surveillance should include extensive baseline total body skin examination (TBSE), including the scalp, oral mucosa, genital area, and nails.
    • Nevi should be checked for any changes in morphology, color, symmetry, and size.
    • Children from families with pathogenic variants may begin screening in late adolescence.
  • Self-examinations at regular intervals either alone or with the assistance of a spouse or relative.
  • Reinforcement of routine sun protective behaviors.
  • Screening of all family members is encouraged.
    • Data suggests those who test negative for a familial variant may still have an increased risk of developing melanoma (due to other shared and environmental risk factors), therefore such relatives should remain under careful dermatologic surveillance and strict sun protection (PMID: 26488006, 19464594).

Melanoma syndromes are relatively rare, and most data regarding follow-up recommendations are based on small studies or expert opinion (PMID: 26892650). Most suggest screening performed at 6-month intervals is adequate, while some advocate for 3-month interval exams (PMID: 26892650). However, formal prospective outcome studies have not been performed and the exact frequency of follow up (3-month, 6-month, or 1-year intervals) remains unclear (PMID: 26892650). When planning follow-up visits for high-risk individuals, it is suggested to weigh out the psychological burden of increased dermatologic surveillance versus its cost effectiveness (PMID: 26892650, 10534637).

Biopsies of skin lesions in the high-risk population should be performed using the same criteria as those used for lesions in the general population. Prophylactic removal of nevi without clinically worrisome characteristics is not recommended. As many individuals in high-risk families have a large number of nevi that continue to develop, complete removal of them all is not feasible. In addition, individuals with increased susceptibility to melanoma may have melanoma develop on normal unaffected skin in the absence of a dysplastic nevus (PMID: 12115352).

While there remains lack of a clear consensus on dermatologic management and surveillance guidelines for individuals with CDKN2A variants, heightened screening may result in early detection and removal of cutaneous lesions at premalignant (dysplastic naevus or melanoma in situ) stages or while melanomas are thin, which is associated with a more favorable prognosis (PMID: 25431349).

Currently, there are no published screening guidelines (age at which screening should be initiated, modalities to be used, frequency of screenings) for individuals who are at increased risk for developing pancreatic cancer; however, screening of high-risk individuals for premalignant pancreatic lesions is currently an active area of research. The National Comprehensive Cancer Network® (NCCN®) Guidelines in Oncology for Pancreatic Adenocarcinoma highlight the promise of pancreatic cancer screening in high-risk patients, which may include individuals with CDKN2A pathogenic variants who have a family history of pancreatic cancer (National Comprehensive Cancer Network. Pancreatic Adenocarcinoma. Version 2.2017). The International Cancer of the Pancreas Screening (CAPS) Consortium recommends pancreatic cancer screening should be considered for individuals who have pathogenic variants in CDKN2A and one or more first-degree relatives with pancreatic cancer (PMID: 23135763). Appropriate candidates may be referred for such surveillance protocols that are being offered on a research basis. The risk of tobacco-related cancers, particularly pancreatic, is significantly increased, and therefore, cigarette smoking be avoided (PMID: 26488006, 25064638, 24935963).

Screening and management for the neural tumors associated with melanoma-neural system tumor (melanoma-NST) syndrome are not established at this time.

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Even though data regarding CDKN2A are limited, knowing if a pathogenic variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding CDKN2A are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to consider implementing proposed screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: May 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CDKN2A* NM_000077.4; NM_058195.3

*CDKN2A: Analysis supports interpretation of the p14 and p16 proteins.