• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit




Associated disorders

The CDK4 gene is associated with autosomal dominant predisposition to cutaneous melanoma (MedGen UID: 268851).

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The CDK4 gene plays an important role in cell cycle regulation. The gene CDK4 encodes the protein cyclin-dependent kinase 4 (CDK4), a member of the serine/threonine protein kinase family. CDK4 is a catalytic subunit of the protein kinase complex, which helps regulate the cell cycle during the G1-phase exit by phosphorylating the protein RB1. Cyclin D-CDK4 complexes are also major integrators of various mitogenic and antimitogenic signals.

CDK4 heterozygotes
MedGen UID: 268851

Clinical condition
Malignant melanoma is considered the most lethal skin cancer if not detected and treated during its early stages (PMID: 26892650, 28121081). Approximately 5-12% of melanoma occurs in patients with a strong family history of melanoma (PMID: 28283772, 16192601). Pathogenic variants in the CDK4 gene have been reported in a limited number of such families to date, and are thought to be a rare cause of inherited susceptibility to melanoma (PMID: 8528263, 23384855). Due to the rarity of pathogenic CDK4 variants, the associated cancer risk is not well defined. One study of 17 families with CDK4 variants reported a 74% risk of melanoma by age 50; the median age of first melanoma diagnosis was 39 years, significantly younger than in the general population (PMID: 23384855). There is an increased frequency of multiple atypical nevi and multiple primary melanomas (PMID: 23384855). Various other cancer types have been reported; however the current evidence is limited and emerging (PMID: 23384855, 15880589).

While pathogenic variants of CDK4 appear to be a rare cause of hereditary melanoma, the clinical presentation including age at diagnosis, cancer location, histology, presence of multiple primary melanomas, and atypical nevi cannot be distinguished from individuals with pathogenic variants in CDKN2A, a more common cause of hereditary melanoma (PMID: 23384855, 15880589).

Gene information
The CDK4 protein product is a member of the Ser/Thr protein kinase family, which is important for cell-cycle G1 phase progression. This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Pathogenic variants in this gene as well as its related proteins including D-type cyclins, p16(INK4a), and Rb, were all found to be associated with tumorigenesis of a variety of cancers (NCBI Gene. Gene ID: 1019. http://www.ncbi.nlm.nih.gov/gene/1019. Accessed April 2017). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers may be increased.

CDK4-related cancer susceptibility has autosomal dominant inheritance. This means that an individual with a pathogenic variant 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.

While there are no established screening or surveillance guidelines for individuals with pathogenic variants in CDK4, the following recommendations have been proposed (PMID: 25431349, 26892650, 26488006, 28283772):

  • 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.
    • Check nevi for any changes in morphology, color, symmetry, and size.
    • Children from families with pathogenic variants in CDK4 may begin screening in late adolescence.
      • Recommendation is supported by observational studies showing that affected individuals tend to develop melanomas at much younger ages.
  • Self-examinations at regular intervals either alone or with the assistance of a spouse or relative
  • Reinforcement of sun protective behaviors
  • Screening of all family members
    • 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).

Because melanoma syndromes are relatively rare, 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 the psychological burden of increased dermatologic surveillance against 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 (PMID: 12115352). Prophylactic removal of nevi without clinically worrisome characteristics is not recommended (PMID: 12115352). As many individuals in high-risk families have a large number of nevi that continue to develop, complete removal is not feasible (PMID: 12115352). In addition, melanoma may 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 inherited melanoma predisposition, heightened screening may result in early detection and removal of cutaneous lesions at premalignant (dysplastic nevus or melanoma in situ) stages or while melanomas are thin, which is associated with a more favorable prognosis (PMID: 25431349).

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 CDK4 is still emerging, 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 CDK4 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 diligently follow standard 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, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. 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
CDK4 NM_000075.3