• 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



CMM8; MI; WS2; WS2A; bHLHe32

Associated disorders

The c.952G>A, p.Glu318Lys variant in the MITF gene is associated with autosomal dominant susceptibility to cutaneous malignant melanoma (MedGen UID: 463554). Other pathogenic variants in the MITF gene are associated with autosomal dominant Waardenburg syndrome (MedGen UID: 349786) and Tietz albinism-deafness syndrome (MedGen UID: 98213) but are not analyzed by this assay.

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MITF: Analysis is limited to the NM_000248.3:c.952G>A p.Glu318Lys variant.

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The MITF gene encodes a transcription factor involved in the development, survival, and function of certain cell types, including neural crest-derived melanocytes and optic cup-derived retinal pigment epithelial cells.

MITF heterozygotes
MedGen UID: 463554

Clinical condition
Malignant melanoma is a neoplasm of melanocytes, the cells that produce pigment. Melanoma most often occurs in the skin, but may also affect the eyes, ears, gastrointestinal tract, and oral and genital membranes. Cutaneous melanoma is considered the most lethal skin cancer if not detected and treated during its early stages (PMID: 26892650). Approximately 5-10% of cases are familial (PMID: 26488006). The c.952G>A (p.Glu318Lys) variant in MITF, also known as E318K, is associated with an increased risk of melanoma (PMID: 26488006, 26650189, 26892651, 22012259, 23167872, 22080950, 25803691). The risks are not yet established; however, studies suggest the risk may be 3- to 5-fold higher than the general population risk (PMID: 22012259, 23167872). This variant has been associated with features including high nevi count (>200), fair skin, non-blue eye color, and early-onset melanoma (under age 40) (PMID: 26488006, 26650189, 26892651, 23774529). Additionally, there is evidence to suggest this variant may predispose to fast-growing melanomas (PMID: 26650189).

Studies showed an overrepresentation of renal cell carcinoma in individuals with this variant (PMID: 22012259, 23167872, 26488006, 26892651, 26650189 ); however, the studies were performed on relatively small patient populations and these findings have not been independently replicated. Therefore, the risk for renal cancer in individuals with the MITF E318K variant is currently unknown.

Other pathogenic variants in the MITF gene are associated with autosomal dominant Waardenburg syndrome (MedGen UID: 349786) and Tietz albinism-deafness syndrome (MedGen UID: 98213) but are currently not analyzed by Invitae.

Gene information
The MITF gene encodes a transcription factor involved in cell cycle control and melanogenesis. These functions allow MITF to mediate differentiation and survival of melanocytes while limiting their uncontrolled progression (PMID: 25431349).

Hereditary predisposition to cancer due to the MITF E318K variant has autosomal dominant inheritance. This means that an individual with this variant has a 50% chance of passing it on to their offspring. Once such a variant is detected, it is possible to identify at-risk relatives who can pursue testing. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).

While there are no established screening or surveillance guidelines for individuals with the pathogenic E318K variant in MITF, the following recommendations have been suggested (PMID: 26650189, 26892650):

  • Follow melanoma prevention programs that include:
    • Sun protection strategies
    • Regular formal dermatologic evaluations
    • Monthly self-examination of the skin
      • Consider immediate and urgent dermatologic follow-up for any new lesions due to evidence suggesting the E318K variant may be associated with fast-growing melanomas (PMID: 26650189).
    • Screening of all family members
      • Because 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), such relatives should remain under careful dermatologic surveillance and strict sun protection (PMID: 26488006, 19464594).

While there remains lack of a clear consensus on dermatologic management and surveillance guidelines for individuals at increased risk for melanoma, heightened screening may result in early detection and removal of cutaneous lesions at premalignant or early stages, 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 MITF is preliminary, 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 MITF 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: March 2016

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
MITF* NM_000248.3

*MITF: Analysis is limited to the NM_000248.3:c.952G>A p.Glu318Lys variant.