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POT1 Tumor Predisposition

, MS, CGC, , MS, CGC, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: February 13, 2025.

Estimated reading time: 22 minutes

Summary

Clinical characteristics.

POT1 tumor predisposition (POT1-TPD) is characterized by an increased lifetime risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional solid tumors and hematologic neoplasms (e.g., thyroid cancer) have been reported in individuals with POT1-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of POT1-associated cancers are diagnosed in adulthood.

Diagnosis/testing.

The diagnosis of POT1-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing.

Management.

Treatment of manifestations: The treatments for POT1-TPD tumors are those used in standard practice.

Surveillance: Full skin examination by a dermatologist beginning at age 18 years at least every six months with excision of any lesions suspicious for melanoma; consider exams every three months in individuals with multiple atypical nevi, history of melanoma, and/or family history of melanoma; in addition, monthly self-examination should be encouraged. Annual whole-body MRI beginning at age 18 years, or earlier depending on personal and family history of non-cutaneous, non-brain malignancies. Annual complete blood count with differential beginning at age 18 years to screen for CLL. Annual comprehensive physical examination including examination of lymph nodes. Consider brain MRI every one to two years beginning at age 18 years depending on family history of glioma.

Agents/circumstances to avoid: Tanning bed use and unprotected sun exposure; radiation in diagnostic procedures.

Evaluation of relatives at risk: Molecular genetic testing for the familial POT1 pathogenic variant should be offered to first-degree relatives to identify those who would benefit from early surveillance and intervention. Although molecular genetic testing for POT1-TPD is generally not recommended for at-risk individuals younger than age 18 years, a history of early cancers in the family may warrant predictive testing prior to age 18 years.

Genetic counseling.

POT1-TPD is inherited in an autosomal dominant manner. To date, most individuals diagnosed with POT1-TPD have an affected parent; the proportion of individuals with POT1-TPD caused by a de novo pathogenic variant is unknown. Each child of an individual with POT1-TPD has a 50% chance of inheriting the POT1 pathogenic variant. Clinical manifestations of POT1-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. Once the germline POT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for POT1 tumor predisposition (POT1-TPD) have been published.

Suggestive Findings

POT1-TPD should be suspected in an individual with the following:

  • Multiple cutaneous melanomas
  • One of the POT1-TPD core cancers and a first- or second-degree relative with a confirmed POT1-TPD core cancer. POT1-TPD core cancers include cutaneous melanoma, sarcoma, chronic lymphocytic leukemia, and glioma.
  • A POT1 pathogenic variant identified on somatic tumor tissue testing

Establishing the Diagnosis

The diagnosis of POT1-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous POT1 variant of uncertain significance does not establish or rule out the diagnosis. To date, however, most POT1 variants are classified as variants of uncertain significance due to insufficient data according to ACMG classification criteria. Due to limited evidence currently available, decision making should rely on clinical history, family history, segregation of the variant, and in silico analysis within the family.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

Single-gene testing. Sequence analysis of POT1 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A hereditary cancer multigene panel that includes POT1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of POT1-TPD, some panels for melanoma, brain tumors, and/or hereditary cancer panels may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in POT1 Tumor Predisposition

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
POT1 Sequence analysis 398% 4
Gene-targeted deletion/duplication analysis 52% 4
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

Clinical Characteristics

Clinical Description

POT1 tumor predisposition (POT1-TPD) is associated with an increased risk for multiple cutaneous melanomas, sarcomas (particularly cardiac angiosarcomas), chronic lymphocytic leukemia (CLL), and gliomas. Additional cancers have been reported in individuals with a germline POT1 pathogenic variant. However, due to limited data it is unclear if these cancers are specifically associated with POT1 germline pathogenic variants. The general experience, however, is that there is a great diversity of tumor types within and between families.

Cutaneous melanoma is the most commonly reported malignancy in individuals with POT1-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years [Robles-Espinoza et al 2014, Shi et al 2014]. Multiple synchronous or metachronous primary cutaneous melanomas are common, with reports ranging from two primary melanomas to up to 20 primary melanomas [Robles-Espinoza et al 2014; Maas et al 2024; T Else, personal observation]. The time between diagnoses of first and second melanoma varies significantly (average: ~9 years).

Sarcoma. Pathogenic germline POT1 variants have been identified in individuals and families with sarcomas, with some families meeting Li-Fraumeni-like (LFL) criteria. In particular, POT1 pathogenic variant p.Arg117Cys has been reported in individuals with cardiac angiosarcoma and cardiac sarcoma [Calvete et al 2017]. Other individuals and families with POT1-TPD have developed osteosarcoma and non-cardiac angiosarcoma [Calvete et al 2015, Herrera-Mullar et al 2023, Abu Shtaya et al 2024, Baptista-Freitas et al 2024].

CLL. Disease-associated POT1 variants have been identified in rare instances of familial CLL. POT1 variants have been identified on somatic testing of CLL (tumor tissue); germline POT1 molecular testing can distinguish somatic and germline variants.

Glioma. Two families with more than one individual with glioma were found to have a germline POT1 pathogenic variant [Bainbridge et al 2014]. One or more individuals in these families presented with oligodendroglioma, suggesting a glioma type-specific susceptibility in these families.

Thyroid cancer has also been suggested to be part of POT1-TPD [Srivastava et al 2020, DeBoy et al 2024]. Germline POT1 pathogenic variants have been observed in 1.5% of selected individuals with papillary thyroid cancer (PTC), meeting criteria for familial PTC, multifocal PTC, and/or young-onset PTC, and 0.7% of unselected individuals with PTC [DeBoy et al 2024]. Individuals with a germline POT1 pathogenic variant had ultra-long telomere length. The pedigrees were felt to demonstrate genetic anticipation, as successive generations had longer telomere length than their parents and developed more cancers at younger ages.

Clonal hematopoiesis. DeBoy et al [2024] found that excessively long telomeres in POT1 heterozygotes conferred a predisposition to lymphoid and myeloid clonal hematopoiesis. Twenty-eight percent (5/18) of individuals with a POT1 pathogenic variant had a T-cell clonality, including cutaneous T-cell lymphoma and large T-cell lymphoma. Sixty-seven percent (8/12) had clonal hematopoiesis of indeterminate potential. Of note, Lim et al [2022] found POT1 germline variants in 1% of individuals with myeloproliferative neoplasms.

Other cancers. Several other benign and malignant neoplasias have been reported in individuals with a germline POT1 variant [T Else, personal observation]; data are too limited to determine if the POT1 variant is causative.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been confirmed.

The p.Arg117Cys POT1 variant has been reported in three families with LFL syndrome in which members had cardiac angiosarcoma, in one family with LFL syndrome in which a member had breast angiosarcoma, and in one individual with cardiac sarcoma in the absence of family history [Calvete et al 2015, Calvete et al 2017].

Penetrance

The penetrance of POT1-TPD is currently unknown. Initial studies suggest a very high penetrance but are subject to a selection bias for research cohorts/families. In more than half of reported families only the proband was tested. Many individuals with germline POT1 variants were ascertained based on a strong family history of cancer from tumor-specific consortiums (e.g., The Gliogene Consortium, UK National Study of Colorectal Cancer Genetics, UK Familial Melanoma Study).

Prevalence

The prevalence of POT1-TPD is currently unknown. However, studies in individuals with familial melanoma suggest that 2.4% have a germline POT1 variant [Robles-Espinoza et al 2014, Shi et al 2014], and 0.5% of melanoma cases may be attributed to POT1-TPD [Simonin-Wilmer et al 2023].

A POT1 founder variant (p.Ser270Asn) has been identified in families from the Romagna region of Italy [Shi et al 2014]. To date, prevalence of this variant in this population is unknown.

Differential Diagnosis

Other genes known to be associated with predisposition to cutaneous melanoma, sarcoma, and/or glioma are listed in Table 2.

Table 2.

Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of POT1 Tumor Predisposition

Cancer Type(s)Gene(s)Tumor Predisposition Syndrome / Comment
Cutaneous melanoma BAP1 BAP1 tumor predisposition syndrome
BRCA2 BRCA1- and BRCA2-associated hereditary breast and ovarian cancer
CDK4 Susceptibility to cutaneous malignant melanoma 3 (OMIM 609048)
CDKN2A Hereditary melanoma/pancreatic cancer syndrome (OMIM 606719)
MITF Susceptibility to cutaneous malignant melanoma 8 (OMIM 614456)
PTEN PTEN hamartoma tumor syndrome (incl Cowden syndrome)
TERT Susceptibility to cutaneous malignant melanoma 9 (OMIM 615134)
Sarcoma & glioma TP53 Li-Fraumeni syndrome
Five cancer types account for the majority of Li-Fraumeni syndrome tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, & soft-tissue sarcomas.
Glioma NF1 Neurofibromatosis 1
NF2 NF2-related schwannomatosis
EPCAM
MLH1
MSH2
MSH6
PMS2
Lynch syndrome
Constitutional mismatch repair deficiency, an autosomal recessive variant of Lynch syndrome, is associated w/biallelic pathogenic variants in MLH1, MSH2, MSH6, or PMS2.

Management

No clinical practice guidelines for POT1 tumor predisposition syndrome (POT1-TPD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with POT1-TPD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. The majority of POT1-associated cancers are diagnosed in adulthood. Therefore, screening should generally begin at age 18 years (see Evaluation of Relatives at Risk.)

Table 3.

POT1 Tumor Predisposition: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment 1
Cutaneous
melanoma
Full skin exam by dermatologistBeginning at age 18 yrs
Sarcoma
(incl cardiac & breast angiosarcoma)
Whole-body MRI
Chronic
lymphocytic
leukemia
  • CBC w/differential
  • Comprehensive physical exam incl lymph nodes
  • Review of whole-body MRI for enlarged lymph nodes
Beginning at age 18 yrs (See Surveillance.)
Brain tumor
(glioma)
Consider brain MRI w/& w/o contrast.Beginning at age 18 yrs
Genetic counseling By genetics professionals 2To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of POT1-TPD to facilitate medical & personal decision making

POT1-TPD = POT1 tumor predisposition; MOI = mode of inheritance

1.

A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a POT1 pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.

2.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

The treatments for POT1-TPD tumors are those used in standard practice.

Surveillance

There are no published guidelines for surveillance for individuals with POT1-TPD. Decisions regarding individual surveillance protocols should be based on the emerging phenotypic spectrum of POT1-TPD, as well as the affected individual's personal and family history. In addition, individuals should be educated regarding general signs and symptoms of malignant diseases and advised to seek medical attention with any concerning findings. Due to the similarity to Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome with tumors in multiple organ systems in certain families, it seems appropriate to employ screening similar to that used in LFS.

Table 4.

POT1 Tumor Predisposition: Recommended Surveillance

System/ConcernEvaluationFrequency 1
Cutaneous
melanoma
Dermatologic exam
  • At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma
  • Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma.
  • Encourage monthly self-exam.
Sarcoma
(incl cardiac & breast angiosarcoma)
Whole-body MRI
  • Annually beginning at age 18 yrs
  • Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies.
Chronic
lymphocytic
leukemia
CBC w/differentialAnnually beginning at age 18 yrs
Comprehensive physical exam incl lymph nodesAnnually
Whole-body MRI for enlarged lymph nodesAnnually beginning at age 18 yrs
Brain tumor
(glioma)
Consider brain MRI. 2Every 1-2 years depending on family history beginning at age 18 yrs
1.

A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a POT1 pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.

2.

The initial brain MRI should be done with contrast, and subsequent brain MRIs may be done without contrast if the previous MRI was normal and there are no new neurologic manifestations [Kratz et al 2017].

Agents/Circumstances to Avoid

To date, there is no evidence that UV light contributes to the pathogenesis of POT1-TPD-associated melanoma. However, individuals with POT1-TPD should be counseled against tanning bed use, as well as unprotected sun exposure, which are known risk factors for melanoma development.

It is currently unknown whether ionizing radiation poses an increased risk to individuals with POT1-TPD, but because of the need for lifelong surveillance, it seems reasonable to avoid radiation in diagnostic procedures and instead recommend MRI or ultrasonography.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of first-degree relatives of an affected individual by molecular genetic testing for the POT1 pathogenic variant in the family in order to identify those who would benefit from screening for POT1-associated cancers. Early recognition of cancers associated with POT1 tumor predisposition (POT1-TPD) may allow for timely intervention and improved final outcome.

In general, molecular genetic testing for POT1-TPD is not recommended for at-risk individuals younger than age 18 years. However, a history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a POT1 pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

POT1 tumor predisposition (POT1-TPD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • To date, most individuals diagnosed with POT1-TPD have an affected parent. An affected parent may have POT1-related tumors that differ from those of the proband.
  • Some individuals diagnosed with POT1-TPD have the disorder as the result of a de novo germline pathogenic variant. The proportion of individuals with POT1-TPD caused by a de novo pathogenic variant is unknown.
  • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for POT1-related cancer surveillance. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, or late onset of the disease in an affected parent. Therefore, de novo occurrence of a POT1 pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the POT1 pathogenic variant.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband has a germline POT1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. It is important to note that clinical manifestations of POT1-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. The types of POT1-related tumors can vary among members of the same family, and current evidence is largely limited to disease-focused studies.
  • If the POT1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for POT1-TPD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with POT1-TPD has a 50% chance of inheriting the POT1 pathogenic variant. Clinical manifestations of POT1-TPD cannot be predicted in heterozygous offspring because the full phenotypic spectrum and penetrance of POT1-TPD are unknown. The types of POT1-related tumors can vary among members of the same family, and current evidence is largely limited to disease-focused studies.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the germline POT1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the POT1 pathogenic variant has been identified in an affected family member.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years). In general, predictive genetic testing for POT1-TPD is not recommended for at-risk individuals younger than age 18 years. However, a history of early-onset cancer in the family may impact surveillance recommendations and warrant predictive genetic testing prior to age 18 years (in unaffected individuals with a POT1 pathogenic variant, surveillance is recommended beginning at age 18 years or two to five years prior to the earliest diagnosis in the family).

In a family with an established diagnosis of POT1-TPD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the POT1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society
    Phone: 800-227-2345
  • CancerCare
    Phone: 800-813-4673
    Email: info@cancercare.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

POT1 Tumor Predisposition: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
POT1 7q31​.33 Protection of telomeres protein 1 POT1 POT1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for POT1 Tumor Predisposition (View All in OMIM)

606478PROTECTION OF TELOMERES 1; POT1
615848TUMOR PREDISPOSITION SYNDROME 3; TPDS3

Molecular Pathogenesis

POT1 encodes protection of telomeres protein 1 (POT1), which together with other components of the telomere-associated protein complex (shelterin), regulates telomerase access to the telomere and suppresses the DNA damage response. POT1 interacts with the single-stranded part of telomeric DNA, an interaction strengthened by POT1 binding to TPP1 [Gong et al 2020]. The protein contains four main domains [Gong et al 2020]:

  • OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA;
  • OB3 fold, which is important for POT1-TPP1 interaction;
  • Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction.

Disruption of single-stranded DNA binding and/or TPP1 binding domains have been shown to lead to lengthened telomeres, which are believed to lead to increased tumorigenesis via three putative mechanisms:

  • Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants;
  • Longer telomeres predispose to fragility and genomic instability;
  • Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1.

Pathogenic variants in POT1 may lead to telomere lengthening, thereby eliminating the need for telomerase activation (observed in ~85% of all cancers) or alternative telomere lengthening. None of these mechanisms of tumorigenesis has been proven.

Mechanism of disease causation. Loss of function. Haploinsufficiency is the proposed underlying mechanism for overall telomere lengthening and the resulting fragile and dysfunctional telomeres [Chen et al 2017, Rice et al 2017, Gong et al 2020].

POT1-specific laboratory technical considerations. Telomere length testing could provide an adjunct clinical laboratory assay, with potential use in further characterizing POT1 variants [Aoude et al 2014, Robles-Espinoza et al 2014]. Increased telomere length (often >99th centile) suggests pathogenicity of certain POT1 variants [Armanios 2022]. It is unknown whether normal telomere length makes pathogenicity less likely.

Table 5.

POT1 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide
Change
Predicted
Protein Change
Comment [Reference]
NM_015450​.2
NP_056265​.2
c.349C>Tp.Arg117CysReported in 3 families w/LFL syndrome & familial cardiac angiosarcoma [Calvete et al 2015]
c.809G>Ap.Ser270AsnFounder variant in Romagna region of Italy [Shi et al 2014]

LFL = Li-Fraumeni-like

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Revision History

  • 13 February 2025 (sw) Comprehensive update posted live
  • 29 October 2020 (sw) Review posted live
  • 12 May 2020 (te) Original submission

References

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