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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>POT1 Tumor Predisposition - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="POT1 Tumor Predisposition">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/02/13">
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<meta name="citation_author" content="Marie-Louise Accardo">
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<meta name="citation_author" content="Jenae Osborne">
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<meta name="citation_author" content="Tobias Else">
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<meta name="citation_pmid" content="33119245">
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<meta name="citation_keywords" content="Protection of telomeres protein 1">
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<meta name="citation_keywords" content="POT1">
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<meta name="citation_keywords" content="POT1 Tumor Predisposition">
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<meta name="DC.Title" content="POT1 Tumor Predisposition">
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<meta name="DC.Contributor" content="Marie-Louise Accardo">
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<meta name="DC.Contributor" content="Jenae Osborne">
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<meta name="DC.Contributor" content="Tobias Else">
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<meta name="description" content="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.">
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<meta name="og:description" content="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.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK563529_"><span class="title" itemprop="name"><i>POT1</i> Tumor Predisposition</span></h1><p class="contribs">Accardo ML, Osborne J, Else T.</p><p class="fm-aai"><a href="#_NBK563529_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 22 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="pot1-tpd.Summary" itemprop="description"><h2 id="_pot1-tpd_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>POT1</i> tumor predisposition (<i>POT1</i>-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 <i>POT1</i>-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years. The majority of <i>POT1</i>-associated cancers are diagnosed in adulthood.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>POT1</i>-TPD is established in a proband with suggestive findings and a heterozygous germline pathogenic variant in <i>POT1</i> identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> The treatments for <i>POT1</i>-TPD tumors are those used in standard practice.</p><p><i>Surveillance:</i> 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.</p><p><i>Agents/circumstances to avoid:</i> Tanning bed use and unprotected sun exposure; radiation in diagnostic procedures.</p><p><i>Evaluation of relatives at risk:</i> Molecular genetic testing for the familial <i>POT1</i> 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 <i>POT1</i>-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.</p></div><div><h4 class="inline">Genetic counseling.</h4><p><i>POT1</i>-TPD is inherited in an autosomal dominant manner. To date, most individuals diagnosed with <i>POT1</i>-TPD have an affected parent; the proportion of individuals with <i>POT1</i>-TPD caused by a <i>de novo</i> pathogenic variant is unknown. Each child of an individual with <i>POT1</i>-TPD has a 50% chance of inheriting the <i>POT1</i> pathogenic variant. Clinical manifestations of <i>POT1</i>-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of <i>POT1</i>-TPD are unknown. Once the germline <i>POT1</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p></div></div><div id="pot1-tpd.Diagnosis"><h2 id="_pot1-tpd_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for <i>POT1</i> tumor predisposition (<i>POT1</i>-TPD) have been published.</p><div id="pot1-tpd.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>POT1</i>-TPD <b>should be suspected</b> in an individual with the following:</p><ul><li class="half_rhythm"><div>Multiple cutaneous melanomas</div></li><li class="half_rhythm"><div>One of the <i>POT1</i>-TPD core cancers and a first- or second-degree relative with a confirmed <i>POT1</i>-TPD core cancer. <i>POT1</i>-TPD core cancers include cutaneous melanoma, sarcoma, chronic lymphocytic leukemia, and glioma.</div></li><li class="half_rhythm"><div>A <i>POT1</i> pathogenic variant identified on somatic tumor tissue testing</div></li></ul></div><div id="pot1-tpd.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>POT1</i>-TPD <b>is established</b> in a proband with <a href="#pot1-tpd.Suggestive_Findings">suggestive findings</a> and a heterozygous germline pathogenic variant in <i>POT1</i> identified by molecular genetic testing (see <a href="/books/NBK563529/table/pot1-tpd.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobpot1tpdTmoleculargenetictestinguse">Table 1</a>).</p><p>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 [<a class="bibr" href="#pot1-tpd.REF.richards.2015.405" rid="pot1-tpd.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a heterozygous <i>POT1</i> variant of uncertain significance does not establish or rule out the diagnosis. To date, however, most <i>POT1</i> 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.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#pot1-tpd.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#pot1-tpd.Option_2">Option 2</a>).</p><div id="pot1-tpd.Option_1"><h4>Option 1</h4><p><b>Single-gene testing</b>. Sequence analysis of <i>POT1</i> 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.</p><p><b>A hereditary cancer multigene panel</b> that includes <i>POT1</i> and other genes of interest (see <a href="#pot1-tpd.Differential_Diagnosis">Differential Diagnosis</a>) 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 <i>GeneReview</i>. Of note, given the rarity of <i>POT1</i>-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.</p><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="pot1-tpd.Option_2"><h4>Option 2</h4><p><b>Comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdTmoleculargenetictestinguse"><a href="/books/NBK563529/table/pot1-tpd.T.molecular_genetic_testing_use/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobpot1tpdTmoleculargenetictestinguse"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.T.molecular_genetic_testing_use"><a href="/books/NBK563529/table/pot1-tpd.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobpot1tpdTmoleculargenetictestinguse">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>POT1</i> Tumor Predisposition </p></div></div></div></div></div><div id="pot1-tpd.Clinical_Characteristics"><h2 id="_pot1-tpd_Clinical_Characteristics_">Clinical Characteristics</h2><div id="pot1-tpd.Clinical_Description"><h3>Clinical Description</h3><p><i>POT1</i> tumor predisposition (<i>POT1</i>-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 <i>POT1</i> pathogenic variant. However, due to limited data it is unclear if these cancers are specifically associated with <i>POT1</i> germline pathogenic variants. The general experience, however, is that there is a great diversity of tumor types within and between families.</p><p><b>Cutaneous melanoma</b> is the most commonly reported malignancy in individuals with <i>POT1</i>-TPD. The age of onset for first primary cutaneous melanoma ranges from 15 to 80 years [<a class="bibr" href="#pot1-tpd.REF.roblesespinoza.2014.478" rid="pot1-tpd.REF.roblesespinoza.2014.478">Robles-Espinoza et al 2014</a>, <a class="bibr" href="#pot1-tpd.REF.shi.2014.482" rid="pot1-tpd.REF.shi.2014.482">Shi et al 2014</a>]. Multiple synchronous or metachronous primary cutaneous melanomas are common, with reports ranging from two primary melanomas to up to 20 primary melanomas [<a class="bibr" href="#pot1-tpd.REF.roblesespinoza.2014.478" rid="pot1-tpd.REF.roblesespinoza.2014.478">Robles-Espinoza et al 2014</a>; <a class="bibr" href="#pot1-tpd.REF.maas.2024.891" rid="pot1-tpd.REF.maas.2024.891">Maas et al 2024</a>; T Else, personal observation]. The time between diagnoses of first and second melanoma varies significantly (average: ~9 years).</p><p><b>Sarcoma.</b> Pathogenic germline <i>POT1</i> variants have been identified in individuals and families with sarcomas, with some families meeting Li-Fraumeni-like (LFL) criteria. In particular, <i>POT1</i> pathogenic variant <a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1pathogenicvariantsrefe">p.Arg117Cys</a> has been reported in individuals with cardiac angiosarcoma and cardiac sarcoma [<a class="bibr" href="#pot1-tpd.REF.calvete.2017.1278" rid="pot1-tpd.REF.calvete.2017.1278">Calvete et al 2017</a>]. Other individuals and families with <i>POT1</i>-TPD have developed osteosarcoma and non-cardiac angiosarcoma [<a class="bibr" href="#pot1-tpd.REF.calvete.2015.8383" rid="pot1-tpd.REF.calvete.2015.8383">Calvete et al 2015</a>, <a class="bibr" href="#pot1-tpd.REF.herreramullar.2023.100937" rid="pot1-tpd.REF.herreramullar.2023.100937">Herrera-Mullar et al 2023</a>, <a class="bibr" href="#pot1-tpd.REF.abu_shtaya.2024.355" rid="pot1-tpd.REF.abu_shtaya.2024.355">Abu Shtaya et al 2024</a>, <a class="bibr" href="#pot1-tpd.REF.baptista_freitas.2024.980" rid="pot1-tpd.REF.baptista_freitas.2024.980">Baptista-Freitas et al 2024</a>].</p><p><b>CLL.</b> Disease-associated <i>POT1</i> variants have been identified in rare instances of familial CLL. <i>POT1</i> variants have been identified on somatic testing of CLL (tumor tissue); germline <i>POT1</i> molecular testing can distinguish somatic and germline variants.</p><p><b>Glioma.</b> Two families with more than one individual with glioma were found to have a germline <i>POT1</i> pathogenic variant [<a class="bibr" href="#pot1-tpd.REF.bainbridge.2014.384" rid="pot1-tpd.REF.bainbridge.2014.384">Bainbridge et al 2014</a>]. One or more individuals in these families presented with oligodendroglioma, suggesting a glioma type-specific susceptibility in these families.</p><p><b>Thyroid cancer</b> has also been suggested to be part of <i>POT1</i>-TPD [<a class="bibr" href="#pot1-tpd.REF.srivastava.2020.1441" rid="pot1-tpd.REF.srivastava.2020.1441">Srivastava et al 2020</a>, <a class="bibr" href="#pot1-tpd.REF.deboy.2024.1114" rid="pot1-tpd.REF.deboy.2024.1114">DeBoy et al 2024</a>]. Germline <i>POT1</i> 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 [<a class="bibr" href="#pot1-tpd.REF.deboy.2024.1114" rid="pot1-tpd.REF.deboy.2024.1114">DeBoy et al 2024</a>]. Individuals with a germline <i>POT1</i> 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.</p><p><b>Clonal hematopoiesis.</b>
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<a class="bibr" href="#pot1-tpd.REF.deboy.2024.1114" rid="pot1-tpd.REF.deboy.2024.1114">DeBoy et al [2024]</a> found that excessively long telomeres in <i>POT1</i> heterozygotes conferred a predisposition to lymphoid and myeloid clonal hematopoiesis. Twenty-eight percent (5/18) of individuals with a <i>POT1</i> 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, <a class="bibr" href="#pot1-tpd.REF.lim.2022.283" rid="pot1-tpd.REF.lim.2022.283">Lim et al [2022]</a> found <i>POT1</i> germline variants in 1% of individuals with myeloproliferative neoplasms.</p><p><b>Other cancers.</b> Several other benign and malignant neoplasias have been reported in individuals with a germline <i>POT1</i> variant [T Else, personal observation]; data are too limited to determine if the <i>POT1</i> variant is causative.</p></div><div id="pot1-tpd.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No clinically relevant genotype-phenotype correlations have been confirmed.</p><p>The <a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1pathogenicvariantsrefe">p.Arg117Cys</a>
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<i>POT1</i> 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 [<a class="bibr" href="#pot1-tpd.REF.calvete.2015.8383" rid="pot1-tpd.REF.calvete.2015.8383">Calvete et al 2015</a>, <a class="bibr" href="#pot1-tpd.REF.calvete.2017.1278" rid="pot1-tpd.REF.calvete.2017.1278">Calvete et al 2017</a>].</p></div><div id="pot1-tpd.Penetrance"><h3>Penetrance</h3><p>The penetrance of <i>POT1</i>-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 <i>POT1</i> 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).</p></div><div id="pot1-tpd.Prevalence"><h3>Prevalence</h3><p>The prevalence of <i>POT1</i>-TPD is currently unknown. However, studies in individuals with familial melanoma suggest that 2.4% have a germline <i>POT1</i> variant [<a class="bibr" href="#pot1-tpd.REF.roblesespinoza.2014.478" rid="pot1-tpd.REF.roblesespinoza.2014.478">Robles-Espinoza et al 2014</a>, <a class="bibr" href="#pot1-tpd.REF.shi.2014.482" rid="pot1-tpd.REF.shi.2014.482">Shi et al 2014</a>], and 0.5% of melanoma cases may be attributed to <i>POT1</i>-TPD [<a class="bibr" href="#pot1-tpd.REF.simoninwilmer.2023.692" rid="pot1-tpd.REF.simoninwilmer.2023.692">Simonin-Wilmer et al 2023</a>].</p><p>A <i>POT1</i> founder variant (<a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1pathogenicvariantsrefe">p.Ser270Asn</a>) has been identified in families from the Romagna region of Italy [<a class="bibr" href="#pot1-tpd.REF.shi.2014.482" rid="pot1-tpd.REF.shi.2014.482">Shi et al 2014</a>]. To date, prevalence of this variant in this population is unknown.</p></div></div><div id="pot1-tpd.Genetically_Related_Allelic_Dis"><h2 id="_pot1-tpd_Genetically_Related_Allelic_Dis_">Genetically Related (Allelic) Disorders</h2><p>Homozygosity for the p.Ser322Leu variant, which is not currently considered a pathogenic variant for <i>POT1</i> tumor predisposition syndrome (<i>POT1</i>-TPD), has been described in two sibs with the diagnosis of Coats plus syndrome (a telomere biology disorder; see <a href="/books/n/gene/dkc/?report=reader">Dyskeratosis Congenita and Related Telomere Biology Disorders</a>).</p><p>A germline heterozygous <i>POT1</i> variant p.Leu259Ser variant was reported in seven relatives (four confirmed on molecular testing, three obligate heterozygotes) with idiopathic pulmonary fibrosis, liver disease, and/or lung cancer [<a class="bibr" href="#pot1-tpd.REF.kelich.2022.e20211681" rid="pot1-tpd.REF.kelich.2022.e20211681">Kelich et al 2022</a>]. Two relatives had telomere length below the 10th centile and two others below the 1st centile. The pedigree was felt to demonstrate genetic anticipation. This variant is not currently considered a pathogenic variant for <i>POT1</i>-TPD. The disease mechanism of this allelic disorder is likely associated with shortened telomeres.</p><p><b>Sporadic cancers.</b> Somatic <i>POT1</i> pathogenic variants have been reported in 3.5% of individuals with chronic lymphocytic leukemia (CLL) and are frequently identified on tumor tissue testing in aggressive forms of CLL [<a class="bibr" href="#pot1-tpd.REF.ramsay.2013.526" rid="pot1-tpd.REF.ramsay.2013.526">Ramsay et al 2013</a>]. Because <i>POT1</i> variants arise early in CLL pathogenesis, they are believed to function as drivers in disease progression. Loss of heterozygosity rarely occurs [<a class="bibr" href="#pot1-tpd.REF.ramsay.2013.526" rid="pot1-tpd.REF.ramsay.2013.526">Ramsay et al 2013</a>, <a class="bibr" href="#pot1-tpd.REF.calvete.2015.8383" rid="pot1-tpd.REF.calvete.2015.8383">Calvete et al 2015</a>]. Somatic variants in <i>POT1</i> have been reported in many solid and hematologic neoplasms.</p></div><div id="pot1-tpd.Differential_Diagnosis"><h2 id="_pot1-tpd_Differential_Diagnosis_">Differential Diagnosis</h2><p>Other genes known to be associated with predisposition to cutaneous melanoma, sarcoma, and/or glioma are listed in <a href="/books/NBK563529/table/pot1-tpd.T.autosomal_dominant_tumor_pred/?report=objectonly" target="object" rid-ob="figobpot1tpdTautosomaldominanttumorpred">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdTautosomaldominanttumorpred"><a href="/books/NBK563529/table/pot1-tpd.T.autosomal_dominant_tumor_pred/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobpot1tpdTautosomaldominanttumorpred"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.T.autosomal_dominant_tumor_pred"><a href="/books/NBK563529/table/pot1-tpd.T.autosomal_dominant_tumor_pred/?report=objectonly" target="object" rid-ob="figobpot1tpdTautosomaldominanttumorpred">Table 2. </a></h4><p class="float-caption no_bottom_margin">Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of <i>POT1</i> Tumor Predisposition </p></div></div></div><div id="pot1-tpd.Management"><h2 id="_pot1-tpd_Management_">Management</h2><p>No clinical practice guidelines for <i>POT1</i> tumor predisposition syndrome (<i>POT1</i>-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.</p><div id="pot1-tpd.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease in an individual diagnosed with <i>POT1</i>-TPD, the evaluations summarized in <a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec_1/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1tumorpredispositionrec1">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended. The majority of <i>POT1</i>-associated cancers are diagnosed in adulthood. Therefore, screening should generally begin at age 18 years (see <a href="#pot1-tpd.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a>.)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdTpot1tumorpredispositionrec"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobpot1tpdTpot1tumorpredispositionrec"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.T.pot1_tumor_predisposition_rec"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1tumorpredispositionrec">Table 3. </a></h4><p class="float-caption no_bottom_margin"><i>POT1</i> Tumor Predisposition: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="pot1-tpd.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>The treatments for <i>POT1</i>-TPD tumors are those used in standard practice.</p></div><div id="pot1-tpd.Surveillance"><h3>Surveillance</h3><p>There are no published guidelines for surveillance for individuals with <i>POT1</i>-TPD. Decisions regarding individual surveillance protocols should be based on the emerging phenotypic spectrum of <i>POT1</i>-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.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdTpot1tumorpredispositionrec1"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec_1/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobpot1tpdTpot1tumorpredispositionrec1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.T.pot1_tumor_predisposition_rec_1"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec_1/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1tumorpredispositionrec1">Table 4. </a></h4><p class="float-caption no_bottom_margin"><i>POT1</i> Tumor Predisposition: Recommended Surveillance </p></div></div></div><div id="pot1-tpd.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>To date, there is no evidence that UV light contributes to the pathogenesis of <i>POT1</i>-TPD-associated melanoma. However, individuals with <i>POT1</i>-TPD should be counseled against tanning bed use, as well as unprotected sun exposure, which are known risk factors for melanoma development.</p><p>It is currently unknown whether ionizing radiation poses an increased risk to individuals with <i>POT1</i>-TPD, but because of the need for lifelong surveillance, it seems reasonable to avoid radiation in diagnostic procedures and instead recommend MRI or ultrasonography.</p></div><div id="pot1-tpd.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of first-degree relatives of an affected individual by molecular genetic testing for the <i>POT1</i> pathogenic variant in the family in order to identify those who would benefit from screening for <i>POT1</i>-associated cancers. Early recognition of cancers associated with <i>POT1</i> tumor predisposition (<i>POT1</i>-TPD) may allow for timely intervention and improved final outcome.</p><p>In general, molecular genetic testing for <i>POT1</i>-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 <i>POT1</i> pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.</p><p>See <a href="#pot1-tpd.Related_Genetic_Counseling_Issu">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="pot1-tpd.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> 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.</p></div></div><div id="pot1-tpd.Genetic_Counseling"><h2 id="_pot1-tpd_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="pot1-tpd.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p><i>POT1</i> tumor predisposition (<i>POT1</i>-TPD) is inherited in an autosomal dominant manner.</p></div><div id="pot1-tpd.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>To date, most individuals diagnosed with <i>POT1</i>-TPD have an affected parent. An affected parent may have <i>POT1</i>-related tumors that differ from those of the proband.</div></li><li class="half_rhythm"><div>Some individuals diagnosed with <i>POT1</i>-TPD have the disorder as the result of a <i>de novo</i> germline pathogenic variant. The proportion of individuals with <i>POT1</i>-TPD caused by a <i>de novo</i> pathogenic variant is unknown.</div></li><li class="half_rhythm"><div>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 <i>POT1</i>-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, <i>de novo</i> occurrence of a <i>POT1</i> pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the <i>POT1</i> pathogenic variant.</div></li><li class="half_rhythm"><div>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:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband has a germline <i>POT1</i> pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. It is important to note that clinical manifestations of <i>POT1</i>-TPD cannot be predicted in heterozygous family members because the full phenotypic spectrum and penetrance of <i>POT1</i>-TPD are unknown. The types of <i>POT1</i>-related tumors can vary among members of the same family, and current evidence is largely limited to disease-focused studies.</div></li><li class="half_rhythm"><div>If the <i>POT1</i> 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 [<a class="bibr" href="#pot1-tpd.REF.rahbari.2016.126" rid="pot1-tpd.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>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 <i>POT1</i>-TPD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with <i>POT1</i>-TPD has a 50% chance of inheriting the <i>POT1</i> pathogenic variant. Clinical manifestations of <i>POT1</i>-TPD cannot be predicted in heterozygous offspring because the full phenotypic spectrum and penetrance of <i>POT1</i>-TPD are unknown. The types of <i>POT1</i>-related tumors can vary among members of the same family, and current evidence is largely limited to disease-focused studies.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent has the germline <i>POT1</i> pathogenic variant, the parent's family members may be at risk.</p></div><div id="pot1-tpd.Related_Genetic_Counseling_Issu"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#pot1-tpd.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Predictive testing</b> (i.e., testing of asymptomatic at-risk individuals)</p><ul><li class="half_rhythm"><div>Predictive testing for at-risk relatives is possible once the <i>POT1</i> pathogenic variant has been identified in an affected family member.</div></li><li class="half_rhythm"><div>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.</div></li></ul><p><b>Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years).</b> In general, predictive genetic testing for <i>POT1</i>-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 <i>POT1</i> pathogenic variant, surveillance is recommended beginning at age 18 years or two to five years prior to the earliest diagnosis in the family).</p><p>In a family with an established diagnosis of <i>POT1</i>-TPD, it is appropriate to consider testing of symptomatic individuals regardless of age.</p><p><b>Genetic cancer risk assessment and counseling.</b> 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 <a href="https://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Cancer Genetics Risk Assessment and Counseling – for health professionals</a> (part of PDQ<sup>®</sup>, National Cancer Institute).</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>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.</div></li></ul></div><div id="pot1-tpd.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>POT1</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>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.</p></div></div><div id="pot1-tpd.Resources"><h2 id="_pot1-tpd_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>American Cancer Society</b>
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</div><div><b>Phone:</b> 800-227-2345</div><div>
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<a href="http://www.cancer.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cancer.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>CancerCare</b>
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</div><div><b>Phone:</b> 800-813-4673</div><div><b>Email:</b> info@cancercare.org</div><div>
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<a href="http://www.cancercare.org" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">cancercare.org</a>
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</div></li></ul>
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</div><div id="pot1-tpd.Molecular_Genetics"><h2 id="_pot1-tpd_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdmolgenTA"><a href="/books/NBK563529/table/pot1-tpd.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobpot1tpdmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.molgen.TA"><a href="/books/NBK563529/table/pot1-tpd.molgen.TA/?report=objectonly" target="object" rid-ob="figobpot1tpdmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">POT1 Tumor Predisposition: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdmolgenTB"><a href="/books/NBK563529/table/pot1-tpd.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobpot1tpdmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.molgen.TB"><a href="/books/NBK563529/table/pot1-tpd.molgen.TB/?report=objectonly" target="object" rid-ob="figobpot1tpdmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for POT1 Tumor Predisposition (View All in OMIM) </p></div></div><div id="pot1-tpd.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>POT1</i> 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 [<a class="bibr" href="#pot1-tpd.REF.gong.2020.48" rid="pot1-tpd.REF.gong.2020.48">Gong et al 2020</a>]. The protein contains four main domains [<a class="bibr" href="#pot1-tpd.REF.gong.2020.48" rid="pot1-tpd.REF.gong.2020.48">Gong et al 2020</a>]:</p><ul><li class="half_rhythm"><div>OB1 and OB2 (oligosaccharide/oligonucleotide) folds, which facilitate initial interaction with telomeric single-stranded DNA;</div></li><li class="half_rhythm"><div>OB3 fold, which is important for POT1-TPP1 interaction;</div></li><li class="half_rhythm"><div>Holliday junction resolvase-like domain, which is important for POT1-TPP1 interaction.</div></li></ul><p>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:</p><ul><li class="half_rhythm"><div>Longer telomeres could delay replicative senescence, increase the replicative life span of cells, and thus lead to the accumulation of pathogenic variants;</div></li><li class="half_rhythm"><div>Longer telomeres predispose to fragility and genomic instability;</div></li><li class="half_rhythm"><div>Chromosomal aberrations, such as sister telomere fusions, have been reported in cells with abnormal POT1.</div></li></ul><p>Pathogenic variants in <i>POT1</i> 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.</p><p><b>Mechanism of disease causation.</b> Loss of function. Haploinsufficiency is the proposed underlying mechanism for overall telomere lengthening and the resulting fragile and dysfunctional telomeres [<a class="bibr" href="#pot1-tpd.REF.chen.2017.14929" rid="pot1-tpd.REF.chen.2017.14929">Chen et al 2017</a>, <a class="bibr" href="#pot1-tpd.REF.rice.2017.14928" rid="pot1-tpd.REF.rice.2017.14928">Rice et al 2017</a>, <a class="bibr" href="#pot1-tpd.REF.gong.2020.48" rid="pot1-tpd.REF.gong.2020.48">Gong et al 2020</a>].</p><p><b><i>POT1</i>-specific laboratory technical considerations.</b> Telomere length testing could provide an adjunct clinical laboratory assay, with potential use in further characterizing <i>POT1</i> variants [<a class="bibr" href="#pot1-tpd.REF.aoude.2014.dju408" rid="pot1-tpd.REF.aoude.2014.dju408">Aoude et al 2014</a>, <a class="bibr" href="#pot1-tpd.REF.roblesespinoza.2014.478" rid="pot1-tpd.REF.roblesespinoza.2014.478">Robles-Espinoza et al 2014</a>]. Increased telomere length (often >99th centile) suggests pathogenicity of certain <i>POT1</i> variants [<a class="bibr" href="#pot1-tpd.REF.armanios.2022.363" rid="pot1-tpd.REF.armanios.2022.363">Armanios 2022</a>]. It is unknown whether normal telomere length makes pathogenicity less likely.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figpot1tpdTpot1pathogenicvariantsrefe"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobpot1tpdTpot1pathogenicvariantsrefe"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="pot1-tpd.T.pot1_pathogenic_variants_refe"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object" rid-ob="figobpot1tpdTpot1pathogenicvariantsrefe">Table 5. </a></h4><p class="float-caption no_bottom_margin"><i>POT1</i> Pathogenic Variants Referenced in This <i>GeneReview</i> </p></div></div></div></div><div id="pot1-tpd.Chapter_Notes"><h2 id="_pot1-tpd_Chapter_Notes_">Chapter Notes</h2><div id="pot1-tpd.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>13 February 2025 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>29 October 2020 (sw) Review posted live</div></li><li class="half_rhythm"><div>12 May 2020 (te) Original submission</div></li></ul></div></div><div id="pot1-tpd.References"><h2 id="_pot1-tpd_References_">References</h2><div id="pot1-tpd.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="pot1-tpd.REF.abu_shtaya.2024.355">Abu Shtaya
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A, Kedar
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I, Bazak
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L, Basel-Salmon
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L, Barhom
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SF, Naftali
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M, Eskin-Schwartz
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M, Birk
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OS, Polager-Modan
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S, Keidar
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N, Reznick Levi
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G, Levi
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Z, Yablonski-Peretz
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T, Mahamid
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A, Segol
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O, Matar
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R, Bareli
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Y, Azoulay
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N, Goldberg
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Y. A
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<em>POT1</em> founder variant associated with early onset recurrent melanoma and various solid malignancies.
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Genes (Basel). 2024;15:355.
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[<a href="/pmc/articles/PMC10970179/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10970179</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/38540414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 38540414</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pot1-tpd.REF.aoude.2014.dju408">Aoude
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LG, Pritchard
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AL, Robles-Espinoza
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CD, Wadt
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K, Harland
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M, Choi
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J, Gartside
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M, Quesada
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V, Johansson
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P, Palmer
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JM, Ramsay
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AJ, Zhang
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X, Jones
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K, Symmons
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J, Holland
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EA, Schmid
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H, Bonazzi
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V, Woods
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S, Dutton-Regester
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K, Stark
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MS, Snowden
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H, van Doorn
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R, Montgomery
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GW, Martin
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NG, Keane
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TM, López-Otín
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C, Gerdes
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AM, Olsson
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H, Ingvar
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C, Borg
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A, Gruis
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NA, Trent
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JM, Jönsson
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G, Bishop
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DT, Mann
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GJ, Newton-Bishop
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JA, Brown
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KM, Adams
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DJ, Hayward
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NK. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.
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J Natl Cancer Inst.
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2014;107:dju408.
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[<a href="/pmc/articles/PMC4334787/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4334787</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25505254" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25505254</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pot1-tpd.REF.armanios.2022.363">Armanios
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M.
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The role of telomeres in human disease.
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Annu Rev Genomics Hum Genet.
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2022;23:363-81.
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[<a href="/pmc/articles/PMC10111244/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10111244</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/35609925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 35609925</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pot1-tpd.REF.bainbridge.2014.384">Bainbridge
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MN, Armstrong
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GN, Gramatges
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MM, Bertuch
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AA, Jhangiani
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SN, Doddapaneni
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H, Lewis
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L, Tombrello
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J, Tsavachidis
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S, Liu
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Y, Jalali
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A, Plon
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SE, Lau
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CC, Parsons
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DW, Claus
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EB, Barnholtz-Sloan
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J, Il'yasova
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D, Schildkraut
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J, Ali-Osman
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F, Sadetzki
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S, Johansen
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C, Houlston
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RS, Jenkins
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RB, Lachance
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D, Olson
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SH, Bernstein
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JL, Merrell
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RT, Wrensch
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MR, Walsh
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KM, Davis
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FG, Lai
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R, Shete
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S, Aldape
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K, Amos
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CI, Thompson
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PA, Muzny
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DM, Gibbs
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RA, Melin
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BS, Bondy
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ML, et al.
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[<a href="/pmc/articles/PMC7352431/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7352431</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32492864" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32492864</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="pot1-tpd.REF.stenson.2020.1197">Stenson
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PD, Mort
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M, Ball
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EV, Chapman
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M, Evans
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K, Azevedo
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L, Hayden
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M, Heywood
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S, Millar
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DS, Phillips
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AD, Cooper
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DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.
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Hum Genet.
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2020;139:1197-207.
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[<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK563529_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Marie-Louise Accardo</span>, MS, CGC<div class="affiliation small">Division of Genetic Medicine<br />Department of Internal Medicine<br />University of Michigan Medical School<br />Ann Arbor, Michigan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.hcimu.dem@yrnehvm" class="oemail">ude.hcimu.dem@yrnehvm</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jenae Osborne</span>, MS, CGC<div class="affiliation small">Division of Genetic Medicine<br />Department of Internal Medicine<br />University of Michigan Medical School<br />Ann Arbor, Michigan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.hcimu.dem@jeanej" class="oemail">ude.hcimu.dem@jeanej</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Tobias Else</span>, MD<div class="affiliation small">Division of Metabolism, Endocrinology & Diabetes<br />Department of Internal Medicine<br />University of Michigan Medical School<br />Ann Arbor, Michigan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.hcimu.dem@eslet" class="oemail">ude.hcimu.dem@eslet</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">October 29, 2020</span>; Last Update: <span itemprop="dateModified">February 13, 2025</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Accardo ML, Osborne J, Else T. POT1 Tumor Predisposition. 2020 Oct 29 [Updated 2025 Feb 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/focal-dh/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/ppp1r12a-ubm/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobpot1tpdTmoleculargenetictestinguse"><div id="pot1-tpd.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>POT1</i> Tumor Predisposition</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>2</sup> Identified by Method</th></tr></thead><tbody><tr><td headers="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>POT1</i>
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</td><td headers="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">98% <sup>4</sup></td></tr><tr><td headers="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_pot1-tpd.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2% <sup>4</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pot1-tpd.TF.1.1"><p class="no_margin">See <a href="/books/NBK563529/?report=reader#pot1-tpd.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="pot1-tpd.TF.1.2"><p class="no_margin">See <a href="#pot1-tpd.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="pot1-tpd.TF.1.3"><p class="no_margin">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 <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="pot1-tpd.TF.1.4"><p class="no_margin">Data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#pot1-tpd.REF.stenson.2020.1197" rid="pot1-tpd.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="pot1-tpd.TF.1.5"><p class="no_margin">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.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpot1tpdTautosomaldominanttumorpred"><div id="pot1-tpd.T.autosomal_dominant_tumor_pred" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Autosomal Dominant Tumor Predisposition Syndromes of Interest in the Differential Diagnosis of <i>POT1</i> Tumor Predisposition</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.T.autosomal_dominant_tumor_pred/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.T.autosomal_dominant_tumor_pred_lrgtbl__"><table><thead><tr><th id="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cancer Type(s)</th><th id="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Tumor Predisposition Syndrome / Comment</th></tr></thead><tbody><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_1" rowspan="7" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cutaneous melanoma</b>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>BAP1</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bap1-tpds/?report=reader"><i>BAP1</i> tumor predisposition syndrome</a>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>BRCA2</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/brca1/?report=reader"><i>BRCA1</i>- and <i>BRCA2</i>-associated hereditary breast and ovarian cancer</a>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>CDK4</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Susceptibility to cutaneous malignant melanoma 3 (OMIM <a href="https://omim.org/entry/609048" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">609048</a>)</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>CDKN2A</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hereditary melanoma/pancreatic cancer syndrome (OMIM <a href="https://omim.org/entry/606719" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606719</a>)</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>MITF</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Susceptibility to cutaneous malignant melanoma 8 (OMIM <a href="https://omim.org/entry/614456" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">614456</a>)</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>PTEN</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/phts/?report=reader"><i>PTEN</i> hamartoma tumor syndrome</a> (incl Cowden syndrome)</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>TERT</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Susceptibility to cutaneous malignant melanoma 9 (OMIM <a href="https://omim.org/entry/615134" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615134</a>)</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sarcoma & glioma</b>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TP53</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/li-fraumeni/?report=reader">Li-Fraumeni syndrome</a><br />Five cancer types account for the majority of Li-Fraumeni syndrome tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, & soft-tissue sarcomas.</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Glioma</b>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NF1</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/nf1/?report=reader">Neurofibromatosis 1</a>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>NF2</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/nf2/?report=reader"><i>NF2</i>-related schwannomatosis</a>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<i>EPCAM</i>
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<br />
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<i>MLH1</i>
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<br />
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<i>MSH2</i>
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<br />
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<i>MSH6</i>
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<br />
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<i>PMS2</i>
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</td><td headers="hd_h_pot1-tpd.T.autosomal_dominant_tumor_pred_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/hnpcc/?report=reader">Lynch syndrome</a><br />Constitutional mismatch repair deficiency, an autosomal recessive variant of Lynch syndrome, is associated w/biallelic pathogenic variants in <i>MLH1</i>, <i>MSH2</i>, <i>MSH6</i>, or <i>PMS2</i>.</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobpot1tpdTpot1tumorpredispositionrec"><div id="pot1-tpd.T.pot1_tumor_predisposition_rec" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p><i>POT1</i> Tumor Predisposition: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.T.pot1_tumor_predisposition_rec_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cutaneous</b>
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<br />
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<b>melanoma</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Full skin exam by dermatologist</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 18 yrs</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sarcoma</b>
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<br />
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<b>(incl cardiac & breast angiosarcoma)</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Whole-body MRI</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Chronic</b>
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<br />
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<b>lymphocytic</b>
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<br />
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<b>leukemia</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>CBC w/differential</div></li><li class="half_rhythm"><div>Comprehensive physical exam incl lymph nodes</div></li><li class="half_rhythm"><div>Review of whole-body MRI for enlarged lymph nodes</div></li></ul>
|
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 18 yrs (See <a href="#pot1-tpd.Surveillance">Surveillance</a>.)</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Brain tumor</b>
|
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<br />
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<b>(glioma)</b>
|
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider brain MRI w/& w/o contrast.</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Beginning at age 18 yrs</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>2</sup></td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of <i>POT1</i>-TPD to facilitate medical & personal decision making</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>POT1</i>-TPD <i>= POT1</i> tumor predisposition; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pot1-tpd.TF.3.1"><p class="no_margin">A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a <i>POT1</i> pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="pot1-tpd.TF.3.2"><p class="no_margin">Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpot1tpdTpot1tumorpredispositionrec1"><div id="pot1-tpd.T.pot1_tumor_predisposition_rec_1" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p><i>POT1</i> Tumor Predisposition: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_tumor_predisposition_rec_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.T.pot1_tumor_predisposition_rec_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency <sup>1</sup></th></tr></thead><tbody><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cutaneous</b>
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<br />
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<b>melanoma</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dermatologic exam</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>At least every 6 mos beginning at age 18 yrs w/excision of any lesions suspicious for melanoma</div></li><li class="half_rhythm"><div>Consider every 3 mos in persons w/multiple atypical nevi, history of melanoma, &/or family history of melanoma.</div></li><li class="half_rhythm"><div>Encourage monthly self-exam.</div></li></ul>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Sarcoma</b>
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<br />
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<b>(incl cardiac & breast angiosarcoma)</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Whole-body MRI</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Annually beginning at age 18 yrs</div></li><li class="half_rhythm"><div>Consider earlier depending on personal & family history of non-cutaneous, non-brain malignancies.</div></li></ul>
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</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_1" rowspan="3" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Chronic</b>
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<br />
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<b>lymphocytic</b>
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<br />
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<b>leukemia</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC w/differential</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually beginning at age 18 yrs</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Comprehensive physical exam incl lymph nodes</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Whole-body MRI for enlarged lymph nodes</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually beginning at age 18 yrs</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Brain tumor</b>
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<br />
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<b>(glioma)</b>
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</td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider brain MRI. <sup>2</sup></td><td headers="hd_h_pot1-tpd.T.pot1_tumor_predisposition_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 1-2 years depending on family history beginning at age 18 yrs</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="pot1-tpd.TF.4.1"><p class="no_margin">A history of early-onset cancer in the family may warrant predictive testing prior to age 18 years. In unaffected individuals with a <i>POT1</i> pathogenic variant, screening should begin at age 18 years or two to five years earlier than the earliest diagnosis in the family.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="pot1-tpd.TF.4.2"><p class="no_margin">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 [<a class="bibr" href="#pot1-tpd.REF.kratz.2017.e38" rid="pot1-tpd.REF.kratz.2017.e38">Kratz et al 2017</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpot1tpdmolgenTA"><div id="pot1-tpd.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>POT1 Tumor Predisposition: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_pot1-tpd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_pot1-tpd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_pot1-tpd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_pot1-tpd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_pot1-tpd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_pot1-tpd.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/25913" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>POT1</i>
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</a>
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</td><td headers="hd_b_pot1-tpd.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=25913" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">7q31<wbr style="display:inline-block"></wbr>​.33</a>
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</td><td headers="hd_b_pot1-tpd.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/Q9NUX5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Protection of telomeres protein 1</a>
|
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</td><td headers="hd_b_pot1-tpd.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=POT1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">POT1</a>
|
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</td><td headers="hd_b_pot1-tpd.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=POT1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">POT1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="pot1-tpd.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
|
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chromosome locus from
|
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
|
<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobpot1tpdmolgenTB"><div id="pot1-tpd.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for POT1 Tumor Predisposition (<a href="/omim/606478,615848" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
|
<a href="/omim/606478" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">606478</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PROTECTION OF TELOMERES 1; POT1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<a href="/omim/615848" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">615848</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TUMOR PREDISPOSITION SYNDROME 3; TPDS3</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobpot1tpdTpot1pathogenicvariantsrefe"><div id="pot1-tpd.T.pot1_pathogenic_variants_refe" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p><i>POT1</i> Pathogenic Variants Referenced in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK563529/table/pot1-tpd.T.pot1_pathogenic_variants_refe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__pot1-tpd.T.pot1_pathogenic_variants_refe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide<br />Change</th><th id="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted<br />Protein Change</th><th id="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_1" rowspan="2" scope="rowgroup" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_015450.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_015450<wbr style="display:inline-block"></wbr>​.2</a>
|
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<br />
|
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_056265.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_056265<wbr style="display:inline-block"></wbr>​.2</a>
|
|
</td><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.349C>T</td><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg117Cys</td><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reported in 3 families w/LFL syndrome & familial cardiac angiosarcoma [<a class="bibr" href="#pot1-tpd.REF.calvete.2015.8383" rid="pot1-tpd.REF.calvete.2015.8383">Calvete et al 2015</a>]</td></tr><tr><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.809G>A</td><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser270Asn</td><td headers="hd_h_pot1-tpd.T.pot1_pathogenic_variants_refe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Founder variant in Romagna region of Italy [<a class="bibr" href="#pot1-tpd.REF.shi.2014.482" rid="pot1-tpd.REF.shi.2014.482">Shi et al 2014</a>]</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">LFL = Li-Fraumeni-like</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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