Associated disorders

The POT1 gene is associated with autosomal dominant cutaneous melanoma (PMID: 24686846, 24686849, 26337759). Additionally, there is preliminary evidence supporting a correlation with autosomal dominant glioma (PMID: 25482530, 25524796, 26634384) and cardiac angiosarcoma (PMID: 26403419).

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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.

POT1 heterozygotes
MedGen UID: 320506

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 CMM (PMID: 24685846, 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 lifetime, 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 Invitae’s 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 limited 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. POT1 directly binds to the telomeres, regulating 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 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).

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 the age at which 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 against 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 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 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: September 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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
POT1 NM_015450.2