• 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




Associated disorders

The POT1 gene is associated with autosomal dominant cutaneous melanoma (PMID: 24686846, 24686849, 26337759).

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Invitae tests that include this gene:

Telomeres mark the ends of chromosomes, and their length is tightly regulated by a variety of functional RNA products, as well as proteins. The POT1 gene encodes a translated member of the Shelterin complex that is responsible for obscuring telomeres from elements of the cellular machinery which would otherwise degrade them.

OMIM: 606478

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 malignant melanoma (CMM) 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). Of these familial cases, approximately half can be attributed to pathogenic variants in known hereditary predisposition genes including CDKN2A, CDK4, and BAP1; however, a large proportion of CMM-predisposing genes remain unidentified (PMID: 24784786, 24686849).

POT1 has recently been identified as susceptibility gene for familial, adult-onset CM (PMID: 24686846, 24686849). While gene-specific risks are not yet established, individuals with a pathogenic variant in POT1 appear to develop melanoma at an earlier age compared to sporadic cases (PMID: 24685846). In addition, these variants appear to be highly penetrant (PMID: 26337759). While individuals with a pathogenic variant in POT1 will not necessarily develop cancer in their lifetimes, their risk of cancer is increased over that of the general population.

There is emerging data to suggest that POT1 may be associated with glioma and cardiac angiosarcoma and therefore this gene is available as a “preliminary evidence” gene on the Invitae Nervous System/Brain Cancer Panel (PMID: 25524796, 26634384) and Sarcoma Panel (PMID: 26403419). 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 preliminary-evidence genes.

Gene information
Protection of telomeres 1 (POT1) is a component of the telomeric shelterin complex that directly binds to single-stranded telomeric repeats. POT1 protects the telomeres by preventing them from being mistakenly recognized as deleterious DNA breaks. By directly binding to the telomeres, POT1 regulates telomerase function and length (PMID: 26337759, 24784786, 24685846). In human cell lines, loss of POT1 expression induces telomere lengthening (PMID: 25482530). Individuals with pathogenic POT1 variants have been found to have longer telomeres, a feature known as a melanoma risk factor (PMID: 24784786).

Pathogenic variants in POT1 have autosomal dominant inheritance (PMID: 24784786). This means that an individual with a pathogenic variant in POT1 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 can occur spontaneously (i.e., an individual with a pathogenic variant in POT1 has parents who do not have it).

While there are no established screening or surveillance guidelines for individuals with pathogenic variants in POT1, the following recommendations are suggested for cases of familial melanoma (PMID: 25431349, 26892650, 26488006):

  • minimize exposure to ultraviolet radiation
  • encourage routine skin self-examinations
  • regular formal dermatological screening

Because data suggest 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).

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).

Because melanoma syndromes are relatively rare, most data regarding follow-up recommendations and at what age to initiate surveillance are based on small studies or expert opinion (PMID: 26892650). Most suggest screening performed at 6-month intervals is adequate, while some suggest 3-month interval exams; however, formal prospective outcome studies have not been performed (PMID: 26892650). The exact frequency of follow up (3-month, 6-month, or 1-year intervals) remains unclear. When planning follow-up visits for high risk individuals, it is suggested to weigh the psychological burden of increased dermatologic surveillance versus its cost effectiveness (PMID: 26892650, 10534637). While there remains lack of a clear consensus on dermatologic management and surveillance, 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 POT1 is preliminary in some cases, 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 POT1 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: October 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
POT1 NM_015450.2