Description 
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndromes (PHTS) are primarily characterized by hamartomatous tumors (disorganized growths of native cells in native tissues) caused by PTEN germline mutations. PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (PLS) (Charis Eng, 2016; Stanich, 2021).

Regulatory Status
No FDA-approved tests were found regarding the assessment of hamartomas. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy

All major and minor criteria are defined in Note 1

1. Genetic counseling for PTEN mutation testing is considered MEDICALLY NECESSARY and is recommended.
2. Genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY to confirm the diagnosis when a patient has clinical signs of Cowden Syndrome/PTEN hamartoma tumor syndrome:
   1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas; OR
   2. Two major and three minor criteria; OR 
   3. Three major and two minor criteria, in an individual without macrocephaly
3. Genetic testing for a PTEN mutationis considered MEDICALLY NECESSARY in individuals not meeting the clinical diagnostic criteria for Cowden Syndrome/PTEN hamartoma tumor syndrome with a personal history of any one of the following:
   1. Adult Lhermitte-Duclos disease (cerebellar tumors)
   2. Autism spectrum disorder and macrocephaly
   3. Two or more biopsy-proven trichilemmomas
   4. Two or more major criteria (one must be macrocephaly)
   5. Three major criteria without macrocephaly
   6. One major and > 3 minor criteria 
   7. > 4 minor criteria 
4. Genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY in individuals with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS).
5. Genetic Testing for a PTEN mutation is considered MEDICALLY NECESSARY in at-risk individuals with a relative with a clinical diagnosis of Cowden Syndrome/PTEN Hamartoma Tumor syndrome or Bannayan-Riley-Ruvalcaba syndrome (BRRS) for whom testing has not been performed AND with either one of the following criteria:
   1. Any one major criterion, OR
   2. Two minor criteria 
6. In first-degree relatives of an individual with a known PTEN mutation, genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY.
   1. Comprehensive PTEN mutation testing is considered MEDICALLY NECESSARY if the familial pathogenic/likely pathogenic variant is not known.
7. Genetic testing for a PTEN mutation is considered MEDICALLY NECESSARY in individuals with PTEN pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline analysis.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

1. Genetic testing for a PTEN mutation is investigational/unproven and therefore considered NOT MEDICALLY NECESSARY for all other indications.

Note 1: The NCCN provides the following major and minor testing criteria for Cowden Syndrome/PTEN Hamartoma Tumor Syndrome (Category 2A recommendation: based on lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate):

Major Testing Criteria

• Breast cancer
• Endometrial cancer
• Follicular thyroid cancer
• Multiple GI hamartomas or ganglioneuromas
• Macrocephaly (megalocephaly) (i.e., ≥ 97%, 58 cm in adult female, 60 cm in adult male)
• Macular pigmentation of glans penis
• Mucocutaneous lesions (any of the following):
  • One biopsy-proven trichilemmoma
  • Multiple palmoplantar keratoses
  • Multifocal or extensive oral mucosal papillomatosis
  • Multiple cutaneous facial papules (often verrucuous)

Minor Testing Criteria

• Autism spectrum disorder
• Colon cancer
• ≥ 3 Esophageal glycogenic acanthoses
• Lipomas 
• Intellectual disability (i.e., IQ ≤ 75)
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid structural lesions (e.g., adenoma nodule[s], goiter)
• Renal cell carcinoma
• Single GI hamartoma or ganglioneuroma
• Testicular lipomatosis
• Vascular anomalies (including multiple intracranial developmental venous anomalies) 

Table of Terminology

Rationale 
Tumor suppressor genes serve several purposes within the body; these genes are able to regulate cell division, restore DNA errors, and tell cells when to die (a process known as apoptosis). Communication of these processes occurs via various cell signaling pathways. In particular, the tumor suppressor gene known as phosphatase and tensin homolog (PTEN) is an important phosphatase regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and the mechanistic target of rapamycin (mTOR) signaling pathway (Sansal & Sellers, 2004; Stanich, 2021). The PI3K/AKT and mTOR signaling pathways are critical for cell proliferation, cell cycle progression, and apoptosis. 

Loss of function of the PTEN gene contributes to an increased risk of both benign and malignant tumors and is implicated in increased lifetime risks of breast, thyroid, uterine, renal, and other cancers; patients may also display clinical features such as cognitive changes, skin changes, macrocephaly (enlarged head) and intestinal polyposis (Ngeow & Eng, 2020). Further, loss of PTEN gene functionality results in a spectrum of autosomal dominant disorders known PTEN hamartoma tumor syndromes (PHTS); this includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome (PLS) (Charis Eng, 2016). Autism spectrum disorders (ASDs) with macrocephaly and adult Lhermitte-Duclos disease (LDD) have also been associated with PHTS (Pilarski, 2019; Stanich, 2021).

A diagnosis of PHTS is established by identification of a germline pathogenic variant in PTEN via molecular genetic testing. A single-gene sequence analysis will detect up to 80% of CS cases, 60% of BRRS cases, 50% PLS cases, and 20% of PS cases. Deletion and duplication analysis or promoter region analysis may also detect additional cases, but further research is required. In addition to single gene analysis, gene panels or further comprehensive testing may assist with clinical management (C. Eng, 2016). All types of mutations have been reported including missense, nonsense, splice site, insertions, and deletions; therefore, PTEN mutation testing usually requires sequence analysis of the entire coding region and deletion/duplication analysis (Charis Eng, 2016; Marsh et al., 1999). Mutations have also been reported in the PTEN promoter, and a test for mutations in this region of the gene has become clinically available (Stanich, 2021). Mingo et al. (2018) recently found that the pathogenicity of frequent PTEN mutations targeting the N-terminus “may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway.” Germline PTEN mutations are found in approximately 20 to 34% of individuals who meet clinical criteria for CS or who meet criteria for genetic testing (Pilarski, 2019; Pilarski et al., 2011; Tan et al., 2011). This number seems to be highly variable as Giorgianni et al. (2013) state that approximately 80% of CS patients have a PTEN mutation at locus 10q23.2. 

Cowden Syndrome (CS)
CS is defined by multiple hamartomas with a high risk for benign and malignant tumors in the thyroid, breast, and endometrium. Besides multiple hamartomas in a variety of tissues, patients typically exhibit macrocephaly as well as characteristic dermatologic manifestations, such as trichilemmomas (benign tumors originating from hair follicles) and papillomatous papules (wart-like growths) (Garofola & Gross, 2020). For individuals with CS, the lifetime risk of developing breast cancer is as high as 85%; for thyroid cancer, which is usually follicular carcinoma, the lifetime risk is as high as 35%; finally, for endometrial cancer, the risk may reach as high as 28% (Charis Eng, 2016). The estimated prevalence of CS is 1 in 200,000 to 250,000, though it is likely underreported (Stanich, 2021). Of all PHTS, only CS has been documented to confer a predisposition to cancer; however, it has been suggested that any patients with PTEN mutations should be assumed to have cancer risks similar to CS (Stanich, 2021).

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
BRRS is characterized by hamartomas along with macrocephaly, lipomas, and pigmented penile macules. It is also associated with high birth weight, developmental delay or deficiency, proximal muscle myopathy, joint hypermobility, high palate, and scoliosis (Stanich, 2021). Similar mutations in the PTEN gene are found in both CS and BRRS, which are now considered phenotypically distinct presentations of a similar genetic abnormality (Lachlan et al., 2007; Marsh et al., 1999).

PTEN-related Proteus Syndrome (PS)
PS is characterized by hamartomatous overgrowth of multiple tissues with hyperostosis (excessive bone growth), vascular malformations, dysregulation of fatty tissues, connective tissue nevi, and epidermal nevi. Phenotypic features of PS are usually present at birth and progress over an individual’s lifetime (Hobert & Eng, 2009).

Proteus-like Syndrome (PLS)
PLS is undefined but typically refers to individuals with similar clinical features to PS who do not meet the diagnostic criteria (Charis Eng, 2016; Hobert & Eng, 2009). Overall, limited information is available on PLS. Stanich (2021) report that PLS cases typically exhibit “a distinct type of epidermal nevus (also referred to as segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus (SOLAMEN) syndrome or type 2 segmental Cowden syndrome).”

Autism Spectrum Disorders (ASDs)
ASDs are a collection of disorders presenting with common abnormalities associated with social and communication behaviors. A few studies have been published which research the relationship between PTEN mutations and ASDs. Schaefer and Mendelsohn (2013) completed a literature review of at least seven different studies and determined that 15 of 318 (5%) individuals with an ASD diagnosis had a pathogenic PTEN mutation; further, macrocephaly was present in all 15 cases.

Lhermitte-Duclos Disease (LDD)
LDD is a rare disease characteristic of benign tumor development in the granule cells of the cerebellum. It has been reported that “Most LDD patients appear to have a germline loss of the PTEN allele and go on to lose the remaining PTEN allele at some point, thereby allowing abnormal growth of the granule cells” (Giorgianni et al., 2013). LDD often develops in conjunction with CS, but may also develop singularly (Stanich, 2021).

Proprietary Testing
Ambry Genetics, GeneDx, Invitae, and Blueprint Genetics all have genetic tests for PTEN mutations. Invitae and Blueprint Genetics both use a next-generation sequencing (NGS) assay that performs full PTEN gene sequencing and deletion/duplication analysis (Ambry, 2021; Blueprint, 2021; GeneDx, 2018; Invitae, 2021). The Invitae assay “achieves > 99% analytical sensitivity and specificity for single nucleotide variants, insertions, and deletions < 15bp [base pair] in length, and exon-level deletions and duplications.” The Blueprint Genetics NGS sequencing assay for single genes performs similarly with a > 99% specificity and sensitivity for single nucleotide variants, including insertions, deletions, and indels up to 50 bp. The Invitae assay has a clinical sensitivity of 85% for CS, 70% for BRRS, 20 – 50% for Proteus-Like Syndrome, and 10% for PTEN-related macrocephalic autism spectrum disorder. The clinical sensitivity is not provided by Blueprint Genetics; however, clinical sensitivity is said to vary based on patient clinical presentation (Blueprint, 2021; Invitae, 2021).

GeneDx utilizes a PCR-amplified assay with capillary sequencing to confirm variants of clinical or uncertain significance. Their assay also performs deletion/duplication testing using “either exon-level CGH [comparative genomic hybridization] or MLPA [multiplex ligation-dependent probe amplification]. Confirmation of copy number changes is performed by MLPA, qPCR [quantitative polymerase chain reaction], or repeat aCGH [array CGH] analysis.” GeneDx has found that “for those probands with Cowden syndrome, sequence analysis of the coding and promoter regions is expected to detect 47 – 80% of causative variants, while large deletions and duplications have been reported. For individuals with Bannayan-Riley-Ruvalcaba syndrome, ~ 60% of causative pathogenic variants will be detected by sequencing while 11% will be detected by deletion/duplication analysis” (GeneDx, 2018). Ambry Genetics also utilizes a PCR-amplified assay with NGS, as well as Sanger Sequencing for any regions “missing or with insufficient read depth coverage for reliable heterozygous variant detection.” Their assay also performs gross deletion and duplication analysis, with any copy number changes detected from NGS confirmed by targeted chromosomal microarray or MLPA. Their analytical sensitivity is > 99.9% for described mutations in the PTEN gene when present and has an identical clinical sensitivity to that described by Invitae (Ambry, 2021). 

Clinical Utility and Validity 
Yehia et al. (2018) conducted a four-year multicenter study; all participants had suspected BRRS or Cowden/Cowden-like (CS/CS-like) syndromes without PTEN mutations. Exome sequencing and targeted analysis was completed on 59 genes supported by the American College of Medical Genetics and Genomics (ACMG), as well as on 24 additional genes known to be associated with inherited cancer syndromes. “Pathogenic or likely pathogenic cancer susceptibility gene alterations were found in seven of the 87 (8%) CS/CS-like and BRRS patients and included MUTYH, RET, TSC2, BRCA1, BRCA2, ERCC2 and HRAS” (Yehia et al., 2018).

Ngeow et al. (2015) estimated the cost effectiveness of each PTEN mutation detected in CS-like patients using the PTEN Cleveland Clinic (CC) score. This is a risk assessment tool which helps to estimate an individual’s risk of having a PTEN mutation. Several questions are answered through an online survey, and a total risk score between 0 and 100 is provided (CC, 2020). The authors found that the cost to detect one PTEN mutation was between $3720 to $4573 at a CC score of 15 (CC15). The authors also concluded that “In sensitivity analyses, CC15 is robustly the most cost-effective strategy for probands who are younger than 60 years” (Ngeow et al., 2015).

Isik et al. (2020) researched the genotype to phenotype correlation of patients with PTEN mutations. A total of 10 molecularly confirmed PHTS patients participated in this study; these participants originated from seven different families. The authors note that “Macrocephaly was the most common clinical finding, involving all patients. This was followed by skin lesions, neurodevelopmental delay, and pathologic cranial magnetic resonance imaging findings” (Isik et al., 2020). Further, sequencing of the PTEN gene identified seven different PTEN variants; four variants were located in exon five. The authors conclude by highlighting the importance of screening for PTEN mutations in patients with macrocephaly, particularly due to an increased risk of cancer.

Jonker et al. (2020) conducted an extensive literature search to identify evidence to support a thyroid carcinoma surveillance program among children with PHTS. They found that children with PHTS were at an increased risk of developing differentiated thyroid carcinoma (DTC), “with 4 years being the youngest age reported at presentation and FTC [follicular thyroid carcinoma] being overrepresented.” This finding supports genetic testing for PTEN mutations, as that could provide guidance and awareness for potential thyroid cancer development at an early age and reduce morbidity with early diagnosis. “Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%” (Jonker et al., 2020). This recommendation was also supported by Baran et al. (2021), who further retrospectively investigated patients at the Children’s Hospital of Philadelphia with a PHTS diagnosis between January 2003 and June 2019. They found “the most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%),” which also appears to corroborate the physical findings of Isik et al. (2020).

Cummings et al. (2022) conducted a systematic review and meta-analysis of the behavioral and psychological features associated with PTEN mutations and the prevalence of autism spectrum disorder characteristics. Using a random effects model, the researchers estimated a pooled prevalence of ASD at 25%, with frequent reporting of intellectual disability and developmental delay, including issues that pertained globally, to motor, and to speech and language. Less frequently were mentions of emotional difficulties ad impaired cognitive functioning. This indicates 

The International Cowden Consortium Operational Criteria for the Diagnosis of Cowden Syndrome Ver 2000 
The following recommended were provided: 

Pathognomonic criteria

Mucocutaneous lesions 

•  Trichilemmomas, facial 
• Acral keratoses 
• Papillomatous papules 
• Mucosal lesions 

Major criteria 

• Breast carcinoma 
• Thyroid carcinoma (non-medullary), especially follicular thyroid carcinoma 
• Macrocephaly (megalencephaly) (say, > 97th centile) 
• Lhermitte-Duclos disease (LDD) 
• Endometrial carcinoma 

Minor criteria 

• Other thyroid lesions (e.g., adenoma or multinodular goitre) 
• Mental retardation (say, IQ
• GI hamartomas 
• Fibrocystic disease of the breast 
• Lipomas 
• Fibromas 
• Genito-urinary tumours (e.g., renal cell carcinoma, uterine fibroids) or malformation

According to the International Cowden Consortium, an operational diagnosis of Cowden Syndrome is made if the individual meets any of the following:

1. Mucocutaneous lesions alone if: 
   1. there are 6 or more facial papules, of which 3 or more must be trichilemmoma, or 
   2. cutaneous facial papules and oral mucosal papillomatosis, or 
   3. oral mucosal papillomatosis and acral keratoses, or 
   4. palmoplantar keratoses, 6 or more 
2. 2 major criteria but one must include macrocephaly or LDD 
3. 1 major and 3 minor criteria 
4. 4 minor criteria 

According to the International Cowden Consortium, an operational diagnosis of Cowden Syndrome in a family where one person is diagnostic for Cowden syndrome is made if any of the following criteria are met:

1. The pathognomonic mucocutaneous lesion
2. Any one major criterion with or without minor criteria 
3. Two minor criteria

In 2013, Pilarski et al. published revised evidence-based criteria covering the spectrum of PTEN-related clinical disorders. The revised guidelines define the operational diagnosis of PTEN Hamartoma Tumor syndrome in an individual who meets either one of the following:

• Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas; or 
• Two major and three minor criteria

The operational diagnosis in a family where one individual meets the revised PTEN Hamartoma Tumor syndrome clinical diagnostic criteria or has a PTEN mutation is as follows (Pilarski et al., 2013): 

• Any two major criteria with our without minor criteria; or 
• One major and two minor criteria; or 
• Three minor criteria

Pilarski et al. (2013) defined the major and minor criteria as follows:

Major Criteria:

• Breast Cancer 
• Endometrial cancer (epithelial) 
• Thyroid Cancer (follicular) 
• Gastrointestinal hamartomas (including ganglioneuromas, adenomas, hyperplastic polyps; ≥3) 
• Lhermitte-Duclos disease (adult) 
• Macrocephaly (megalocephaly) (i.e., ≥ 97th percentile, 58 cm in adult women, 60 cm in adult men) 
• Macular pigmentation of glans penis 
• Multiple mucocutaneous lesions (any of the following): 
  • Multiple trichilemmomas (≥ 3, at least one biopsy proven) 
  • Acral keratoses (≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules) 4 – GT63 
  • Mucocutaneous neuromas (≥ 3) 
  • Oral papillomas (particularly on tongue and gingiva), multiple (≥ 3) OR biopsy proven OR dermatologist diagnosed

Minor Criteria:

• Autism spectrum disorder 
• Colon cancer 
• ≥ 3 esophageal glycogenic acanthoses 
• Lipomas (≥ 3) 
• Intellectual disability (i.e., IQ ≤ 75) 
• Renal cell carcinoma 
• Testicular lipomatosis 
• Thyroid cancer (papillary or follicular variant of papillary) 
• Thyroid structural lesions (e.g., adenoma, multinodular goiter) 
• Vascular anomalies (including multiple intracranial developmental venous anomalies)

National Comprehensive Cancer Network (NCCN)
The NCCN guidelines for Cowden Syndrome/PTEN Hamartoma Tumor syndrome recommend testing in individuals who meet any of the following criteria:

• “Individual from a family with a known PTEN^t pathogenic variant/likely pathogenic variant
• Individual with a personal history of Bannayan-Riley-Ruvalcaba syndrome (BRRS)
• Individual meeting the clinical diagnostic criteria for CS/PHTS
• Individual not meeting the clinical diagnostic criteria for CS/PHTS with a personal history of:

o    Adult Lhermitte-Duclos disease (cerebellar tumors); or
o    Autism spectrum disorder and macrocephaly; or
o    Two or more biopsy-proven trichilemmomas; or
o    Two or more major criteria (one must be macrocephaly); or
o    Three major criteria, without macrocephaly; or
o    One major and ≥ 3 minor criteria;bb or
o    > 4 minor criteria

• At-risk individual with a relative with a clinical diagnosis of CS/PHTS or BRRS for whom testing has not been performed. The at-risk individual must have the following:
  • Any one major criterion, OR
  • Two minor criteria 
• PTEN pathogenic/likely pathogenic variant detected by tumor profiling on any tumor type in the absence of germline analysis^cc

^tWhen this gene is included as part of a multi-gene panel, an individual does not need to meet these testing criteria if testing criteria on other testing criteria pages are met. 

^bbIf an individual has two or more major criteria, such as breast cancer and nonmedullary thyroid cancer, but does not have macrocephaly, one of the major criteria may be included as one of the three minor criteria to meet testing criteria.

^ccThis should prompt a careful evaluation of personal and family history of the individual to determine the yield of germline sequencing. Somatic PTEN pathogenic/likely pathogenic variants are common in many tumor types in absence of germline pathogenic/likely pathogenic variant.

Major Testing Criteria

• Breast cancer
• Endometrial cancer
• Follicular thyroid cancer
• Multiple GI hamartomas or ganglioneuromasdd
• Macrocephaly (megalocephaly) (i.e., ≥ 97%, 58 cm in adult female, 60 cm in adult male)^ee
• Macular pigmentation of glans penis
• Mucocutaneous lesions^ff (any of the following):
  • One biopsy-proven trichilemmoma
  • Multiple palmoplantar keratoses
  • Multifocal or extensive oral mucosal papillomatosis
  • Multiple cutaneous facial papules (often verrucuous)

Minor Testing Criteria^gg

• Autism spectrum disorder
• Colon cancer
• ≥ 3 Esophageal glycogenic acanthoses
• Lipomas 
• Intellectual disability (i.e., IQ ≤ 75)
• Papillary or follicular variant of papillary thyroid cancer
• Thyroid structural lesions (e.g., adenoma nodule[s], goiter)
• Renal cell carcinoma
• Single GI hamartoma or ganglioneuroma
• Testicular lipomatosis
• Vascular anomalies (including multiple intracranial developmental venous anomalies) 

NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. [In these criteria], the terms males and females refer to sex assigned at birth.

^ddMultiple polyp types are often seen in patients with PHTS, and less commonly may include adenomas, hyperplastic polyps, and other histologies.
^ffThe literature available on mucocutaneous lesions is not adequate to accurately specify the number or extent of mucocutaneous lesions required to be a major criterion for CS/PHTS. Clinical judgment should be used.

^ggInsufficient evidence exists in the literature to include fibrocystic disease of the breast, fibromas, and uterine fibroids as diagnostic criteria” (NCCN, 2022).

“Operational diagnosis in an individual (either of the following):

1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or GI hamartomas; or
2. Two major and three minor criteria.

Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN pathogenic/likely pathogenic variant:

1. Any two major criteria with or without minor criteria; or
2. One major and two minor criteria; or
3. Three minor criteria.” (NCCN, 2022)

ClinGen PTEN Expert Panel 
This expert panel was convened by the ClinGen Hereditary Cancer Clinical Domain Working Group to develop PTEN-specific genetic variant interpretations. A total of 42 variants were included in the following categories: benign/likely benign (BEN/LBEN), pathogenic/likely pathogenic (PATH/LPATH), uncertain significance (VUS), and conflicting (CONF) ClinVar assertions.

The following variants were considered BEN/LBEN: 9C>G, 903G>A, 1026C>A, 1311T>C, 18A>G, 75G>A, 132C>T, 360A>G, 1104T>G, 79+35C>T, 165-13_165-10delGTTT, 254-39G>T, 801+23G>A, and 1026+32T>G.
The following variants were considered PATH/LPATH: 50_51delAA, 511C>T, 892C>T, 964A>T, 987_990delTAAA, 80-1G>C, 165-1G>A, 493-2A>G, 801+1delG, 802-2A>T, 1026+1G, 103A>G, 389G>A, 407G>A, 517C>T, and 737C>T.

The following variants were considered VUS or CONF: 1170C>T, 209+3A>T, 235G>A, 304_306dupAAA, 1052_1054delTAG, 1171C>T, 764G>A, 44G>A, 78C>T, 209+4_209+7delAGTA, 521A>G (Mester et al., 2018).

American College of Medical Genetics (ACMG)
In 2013, the ACMG published guidelines for identifying the etiology of autism spectrum disorders (ASDs). These guidelines state that “PTEN testing [should] be reserved for patients with ASDs with a head circumference above the 98th percentile” (Schaefer & Mendelsohn, 2013). The authors then suggest that of all ASD-related genetic evaluations, about 5% of testing will be due to PTEN mutations.

National Organization for Rare Disorders (NORD) 
The NORD states that “Sotos syndrome is a rare genetic disorder characterized by excessive growth that occurs prior to and after birth (prenatally and postnatally) …. The overlap of neurodevelopmental disabilities and macrocephaly in both PHTS and Sotos syndrome indicates the need for genetic testing to avoid misdiagnosis” (NORD, 2018). Genetic counseling is also suggested.

American College of Gastroenterology (ACG) 
In 2015, the ACG published guidelines on genetic testing and management of hereditary gastrointestinal cancer syndromes. These guidelines clearly state that the “Genetic evaluation of a patient with possible CS should include testing for PTEN mutations … CS is caused by mutations in the PTEN gene. Once a disease-causing mutation is identified in a patient with CS or related conditions, other family members should undergo mutation-specific testing to determine whether the disease is present or absent so that appropriate surveillance can be undertaken” (Syngal et al., 2015). Further, the ACG also notes that “Surveillance in affected or at-risk CS patients should include screening for colon, stomach, small bowel, thyroid, breast, uterine, kidney, and skin (melanoma) cancers (conditional recommendation, low quality of evidence)” (Syngal et al., 2015).
 

References  

1. Ambry. (2021). PTEN-related Disorders. https://www.ambrygen.com/providers/genetic-testing/130/oncology/pten-related-disorders
2. Baran, J. A., Tsai, S. D., Isaza, A., Brodeur, G. M., MacFarland, S. P., Zelley, K., Adams, D. M., Franco, A. T., & Bauer, A. J. (2021). The Clinical Spectrum of PTEN Hamartoma Tumor Syndrome: Exploring the Value of Thyroid Surveillance. Horm Res Paediatr, 1-9. https://doi.org/10.1159/000515731 
3. Blueprint. (2021). PTEN Single Gene Test. https://blueprintgenetics.com/tests/single-gene-tests/pten-single-gene-test-2/
4. CC. (2020). Cleveland Clinic PTEN Risk Calculator. https://www.lerner.ccf.org/gmi/ccscore/
5. Cummings, K., Watkins, A., Jones, C., Dias, R., & Welham, A. (2022). Behavioural and psychological features of PTEN mutations: a systematic review of the literature and meta-analysis of the prevalence of autism spectrum disorder characteristics. J Neurodev Disord, 14(1), 1. https://doi.org/10.1186/s11689-021-09406-w 
6. Eng, C. (2016). PTEN Hamartoma Tumor Syndrome [Text]. GeneReviews. https://doi.org/https://www.ncbi.nlm.nih.gov/books/NBK1488/ 
7. Eng, C. (2016). PTEN Hamartoma Tumor Syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews((R)). University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved. https://www.ncbi.nlm.nih.gov/books/NBK1488/ 
8. Garofola, C., & Gross, G. P. (2020). Cowden Disease (Multiple Hamartoma Syndrome). In StatPearls. StatPearls Publishing LLC. https://www.ncbi.nlm.nih.gov/pubmed/30252240 
9. GeneDx. (2018). PTEN Gene Analysis in PTEN Hamartoma Tumor Syndrome. https://www.genedx.com/wp-content/uploads/crm_docs/info_sheet_brr_cow.pdf
10. Giorgianni, A., Pellegrino, C., De Benedictis, A., Mercuri, A., Baruzzi, F., Minotto, R., Tabano, A., & Balbi, S. (2013). Lhermitte-Duclos disease. A case report. Neuroradiol J, 26(6), 655-660. https://doi.org/10.1177/197140091302600608 
11. Hobert, J. A., & Eng, C. (2009). PTEN hamartoma tumor syndrome: an overview. Genet Med, 11(10), 687-694. https://doi.org/10.1097/GIM.0b013e3181ac9aea 
12. Invitae. (2021). Invitae PTEN-Related Disorders Test. https://www.invitae.com/es/physician/tests/01704/#info-panel-disorders_tested
13. Isik, E., Simsir, O. S., Solmaz, A. E., Onay, H., Atik, T., Aykut, A., Durmaz, A., Cogulu, O., & Ozkinay, F. (2020). Clinical and molecular aspects of PTEN mutations in 10 pediatric patients. Ann Hum Genet. https://doi.org/10.1111/ahg.12380 
14. Jonker, L. A., Lebbink, C. A., Jongmans, M. C. J., Nievelstein, R. A. J., Merks, J. H. M., Nieveen van Dijkum, E. J. M., Links, T. P., Hoogerbrugge, N., van Trotsenburg, A. S. P., & van Santen, H. M. (2020). Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome. Eur Thyroid J, 9(5), 234-242. https://doi.org/10.1159/000508872 
15. Lachlan, K. L., Lucassen, A. M., Bunyan, D., & Temple, I. K. (2007). Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers. J Med Genet, 44(9), 579-585. https://doi.org/10.1136/jmg.2007.049981 
16. Marsh, D. J., Kum, J. B., Lunetta, K. L., Bennett, M. J., Gorlin, R. J., Ahmed, S. F., Bodurtha, J., Crowe, C., Curtis, M. A., Dasouki, M., Dunn, T., Feit, H., Geraghty, M. T., Graham, J. M., Jr., Hodgson, S. V., Hunter, A., Korf, B. R., Manchester, D., Miesfeldt, S., . . . et al. (1999). PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet, 8(8), 1461-1472. 
17. Mester, J. L., Ghosh, R., Pesaran, T., Huether, R., Karam, R., Hruska, K. S., Costa, H. A., Lachlan, K., Ngeow, J., Barnholtz-Sloan, J., Sesock, K., Hernandez, F., Zhang, L., Milko, L., Plon, S. E., Hegde, M., & Eng, C. (2018). Gene-specific criteria for PTEN variant curation: Recommendations from the ClinGen PTEN Expert Panel. Hum Mutat, 39(11), 1581-1592. https://doi.org/10.1002/humu.23636 
18. Mingo, J., Rodriguez-Escudero, I., Luna, S., Fernandez-Acero, T., Amo, L., Jonasson, A. R., Zori, R. T., Lopez, J. I., Molina, M., Cid, V. J., & Pulido, R. (2018). A pathogenic role for germline PTEN variants which accumulate into the nucleus. Eur J Hum Genet. https://doi.org/10.1038/s41431-018-0155-x 
19. NCCN. (2022, 03/09/2022). Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 2.2022 - March 9, 2022. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf
20. Ngeow, J., & Eng, C. (2020). PTEN in Hereditary and Sporadic Cancer. Cold Spring Harb Perspect Med, 10(4). https://doi.org/10.1101/cshperspect.a036087 
21. Ngeow, J., Liu, C., Zhou, K., Frick, K. D., Matchar, D. B., & Eng, C. (2015). Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis. J Clin Oncol, 33(23), 2537-2544. https://doi.org/10.1200/jco.2014.60.3456 
22. NORD. (2018). PTEN Hamartoma Tumor Syndrome. https://rarediseases.org/rare-diseases/pten-hamartoma-tumor-syndrome/
23. Pilarski, R. (2019). PTEN Hamartoma Tumor Syndrome: A Clinical Overview. Cancers (Basel), 11(6). https://doi.org/10.3390/cancers11060844 
24. Pilarski, R., Burt, R., Kohlman, W., Pho, L., Shannon, K. M., & Swisher, E. (2013). Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst, 105(21), 1607-1616. https://doi.org/10.1093/jnci/djt277 
25. Pilarski, R., Stephens, J. A., Noss, R., Fisher, J. L., & Prior, T. W. (2011). Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet, 48(8), 505-512. https://doi.org/10.1136/jmg.2011.088807 
26. Sansal, I., & Sellers, W. R. (2004). The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol, 22(14), 2954-2963. https://doi.org/10.1200/jco.2004.02.141 
27. Schaefer, G. B., & Mendelsohn, N. J. (2013). Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med, 15(5), 399-407. https://doi.org/10.1038/gim.2013.32 
28. Stanich, P. (2021, 12/08/2021). PTEN hamartoma tumor syndrome, including Cowden syndrome. https://www.uptodate.com/contents/pten-hamartoma-tumor-syndromes-including-cowden-syndrome
29. Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L., & Burt, R. W. (2015). ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol, 110(2), 223-262; quiz 263. https://doi.org/10.1038/ajg.2014.435 
30. Tan, M. H., Mester, J., Peterson, C., Yang, Y., Chen, J. L., Rybicki, L. A., Milas, K., Pederson, H., Remzi, B., Orloff, M. S., & Eng, C. (2011). A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet, 88(1), 42-56. https://doi.org/10.1016/j.ajhg.2010.11.013 
31. Yehia, L., Ni, Y., Sesock, K., Niazi, F., Fletcher, B., Chen, H. J. L., LaFramboise, T., & Eng, C. (2018). Unexpected cancer-predisposition gene variants in Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome patients without underlying germline PTEN mutations. PLoS Genet, 14(4), e1007352. https://doi.org/10.1371/journal.pgen.1007352 
     

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward