Clinical Guidance

No clinically relevant genotype-phenotype correlations have been confirmed. The 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 .

Source: GeneReviews — "POT1 Tumor Predisposition"

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).

Source: GeneReviews — "POT1 Tumor Predisposition"

Diagnostic Criteria

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 and a heterozygous germline pathogenic variant in POT1 identified by molecular genetic testing . Note: (1) Per American College of Medical Genetics and Genomics/ Association for Molecular Pathology variant interpretatio...

Source: GeneReviews — "POT1 Tumor Predisposition"

Differential Diagnosis

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

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 (See CDKN2A Cancer Predisposition.)

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)

Source: GeneReviews — "POT1 Tumor Predisposition"

Management Guidelines

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 (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 .)

Table 3.

POT1 Tumor Predisposition: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment1

Cutaneous

melanoma | Full skin exam by dermatologist | Beginning 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 .)

Brain tumor

(glioma) | Consider brain MRI w/ w/o contrast. | Beginning at age 18 yrs

Genetic counseling

| By genetics professionals2 | To 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

Source: GeneReviews — "POT1 Tumor Predisposition"

Clinical Guidance

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.

Source: GeneReviews — "POT1 Tumor Predisposition"

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.

Source: GeneReviews — "POT1 Tumor Predisposition"

Surveillance Guidelines

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

Source: GeneReviews — "POT1 Tumor Predisposition"