Humana Genetic Testing for RASopathy Syndromes Form

RASopathy Syndromes

RASopathy syndromes are a group of genetic conditions with overlapping clinical characteristics and features that arise from gene variations (mutations) in a common mechanism known as the Ras/MAPK cell signaling pathway. This pathway is essential for governing cell functions such as cell growth, maturation and death. Individual RASopathies are rare; however, as a group, they are among the most common genetic conditions.

The RASopathies include, but are not limited to:

• Cardiofaciocutaneous syndrome
• Costello syndrome (also known as faciocutaneoskeletal syndrome)
• Neurofibromatosis type 1 (NF1)
• NF2-related schwannomatosis (NF2)
• Noonan syndrome
• Noonan syndrome with multiple lentigines (brown spots on skin) (formerly known as LEOPARD syndrome)

Genetic Testing for RASopathy Syndromes

Effective Date: 09/28/2023

Revision Date : 09/28/2023

Review Date : 09/28/2023

Policy Number: HUM-0565-003 Page: 2 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Genetic testing may be performed to analyze an individual’s deoxyribonucleic acid (DNA) to detect gene variants to assist in confirming a diagnosis in those who exhibit disease signs and symptoms.

Multigene panels analyze many genes simultaneously and have been proposed to evaluate genes associated with diseases or syndromes. Panels often include medically actionable genes but may also include those with unclear medical management. (Refer to Coverage Limitations section)

Targeted (or focused) multigene panels are also commercially available. These panels limit the number of genes and are targeted to a specific condition. In general multigene panels are not appropriate; however, in rare instances, targeted panel analysis may be applicable.

For information regarding comparative genomic hybridization (CGH) to detect deletions/duplications and/or for full gene sequence analysis for single gene disorders, please refer to Comparative Genomic Hybridization/Chromosomal Microarray Analysis Medical Coverage Policy.

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing

Genetic Testing for RASopathy Syndromes

Effective Date: 09/28/2023

Revision Date : 09/28/2023

Review Date : 09/28/2023

Policy Number: HUM-0565-003 Page: 3 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Retrieved archival tissue

Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Coverage Determination

Any state mandates for genetic testing RASopathy syndromes take precedence over this medical coverage policy.

Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding Plan coverage.

Apply General Criteria for Genetic and Pharmacogenomics Tests when disease- or gene-specific criteria are not available on a medical coverage policy.

For information regarding general criteria for genetic tests, please refer to Genetic Testing Medical Coverage Policy.

CARDIOFACIOCUTANEOUS SYNDROME

Cardiofaciocutaneous Syndrome (Core Genes KRAS, MAP2K1, MAP2K2) – Affected Individual

Humana members may be eligible under the Plan for cardiofaciocutaneous syndrome single gene testing or targeted multigene panel of 12 or fewer genes (81442) that includes the core genes when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested exhibits the following characteristics of cardiofaciocutaneous syndrome; AND
  • Congenital heart disease, at least 1 of the following:
    • Atrial septal defects
    • Bicuspid aortic valve
    • Hypertrophic cardiomyopathy
    • Mitral valve dysplasia
    • Pulmonic stenosis
  • Rhythm disturbances
  • Tricuspid valve dysplasia
  • Ventricular septal defects; AND
  • Craniofacial dysmorphology, at least 1 of the following:
    • Bitemporal narrowing
    • Cupid's bow configuration of the upper lip
    • Deep philtrum
    • Downslanting palpebral fissures
    • Ear lobe creases
    • Epicanthal folds
    • High forehead
    • High-arched palate
    • Hypoplasia of the supraorbital ridges
    • Low-set ears that may be posteriorly rotated
    • Macrocephaly defined as occipitofrontal circumference (OFC or head circumference) less than 2 standard deviations (SDs) above the mean for age and sex determined by a standardized head circumference chart (eg, Centers for Disease Control and Prevention [CDC], World Health Organization [WHO])
    • Ocular hypertelorism
    • Ptosis
    • Relative micrognathia
  • Dermatologic abnormalities, at least 1 of the following:
    • Cafe-au-lait macules
    • Eczema
    • Erythema
    • Hemangiomas
    • Hyperkeratosis of arms, legs and face
    • Ichthyosis
    • Keratosis pilaris
    • Palmoplantar hyperkeratosis over pressure zones
    • Pigmented moles
    • Sparse, curly, fine or thick, woolly or brittle hair
    • Ulerythema ophryogenes
    • Xerosis

Cardiofaciocutaneous Syndrome – KRAS, MAP2K1, MAP2K2 Genes – Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for cardiofaciocutaneous syndrome KFV genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Performed for reproductive decision-making when the individual to be tested is of reproductive age; AND
• Has an affected first-degree relative with a pathogenic or likely pathogenic variant in the KRAS, MAP2K1 or MAP2K2 gene (test KFV).

Genetic Testing for RASopathy Syndromes Effective Date: 09/28/2023 Revision Date : 09/28/2023 Review Date : 09/28/2023 Policy Number: HUM-0565-003 Page: 6 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

COSTELLO SYNDROME

Costello Syndrome (HRAS Gene) – Affected Individual

Humana members may be eligible under the Plan for HRAS gene testing when the Following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested exhibits 2 or more of the following clinical features of Costello syndrome:
  • Coarse facial features
  • Curly or sparse, fine hair
  • Growth failure (failure to thrive) when decreased height velocity (HV) is below the 25th percentile
  • Macrocephaly defined as occipitofrontal circumference (OFC or head circumference) less than 2 standard deviations (SDs) above the mean for age and sex determined by a standardized head circumference chart (eg, Centers for Disease Control and Prevention [CDC], World Health Organization [WHO])
  • Severe postnatal feeding difficulties extending throughout early childhood
  • Short stature defined as height below the 2.3rd percentile (2 SDs or greater)

NEUROFIBROMATOSIS TYPE 1

NF1 (NF1 Gene) – Affected Individual

Humana members may be eligible under the Plan for NF1 gene testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested does not fulfill the Revised Diagnostic Criteria for NF1 or the Diagnostic Criteria for Mosaic NF1 but a definitive diagnosis remains uncertain despite a complete family/personal history, physical examination and conventional diagnostic studies (eg, magnetic resonance imaging [MRI], eye examinations)

NF1 – NF1 Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for NF1 KFV genetic testing for reproductive decision-making when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Performed for reproductive decision-making when the individual to be tested is of reproductive age; AND
• Has an affected first-degree relative with a pathogenic or likely pathogenic variant in the NF1 gene (test KFV).

NEUROFIBROMATOSIS TYPE 2

NF2 (NF2 Gene) – Affected Individual

Humana members may be eligible under the Plan for NF2 gene testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
  • Individual to be tested has a first-degree relative diagnosed with NF2; OR
  • Individual to be tested does not fulfill the Clinical Criteria for NF2 (Revised Manchester Criteria); AND
  • Definitive diagnosis remains uncertain despite a complete family/personal history, physical examination and conventional diagnostic studies (eg, MRI, eye examinations); OR
  • Diagnosed with a solitary meningioma at 25 years of age or younger;

Genetic Testing for RASopathy Syndromes Effective Date: 09/28/2023 Revision Date : 09/28/2023 Review Date : 09/28/2023 Policy Number: HUM-0565-003 Page: 8 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

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• Diagnosed with a solitary nonvestibular schwannoma at 25 years of age or younger; OR
• Diagnosed with a solitary vestibular schwannoma at 20 years of age or younger; OR
• Diagnosed with two or more mengingiomas or ependymomas

NF2 – NF2 Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for NF2 KFV genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has an affected first-degree relative with a pathogenic or likely pathogenic variant in the NF2 gene (test KFV).

NOONAN SYNDROME

Noonan Syndrome (Core Genes KRAS, LZTR1, MRAS, NRAS, PTPN11, SOS1, SOS2, RAF1, RIT1, RRAS2)

Humana members may be eligible under the Plan for Noonan syndrome single gene or targeted multigene panel of 12 or fewer genes (81442) that includes the core genes when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested exhibits at least 1 distinctive facial feature (high forehead, ptosis, widely-spaced eyes that are downslanting, strikingly blue irides, neck webbing, low-set posteriorly rotated ears); AND
  • Congenital heart defects (eg, atrial septal defect, hypertrophic cardiomyopathy, pulmonary stenosis); OR
  • Cryptorchidism; OR
  • First-degree relative diagnosed with or features suggestive of Noonan syndrome; OR
  • Lymphatic dysplasia; OR
  • Mild developmental delay; OR
  • Pectus carinatum/excavatum; OR
  • Short stature below 10th percentile

Noonan Syndrome – KRAS, LZTR1, MRAS, NRAS, PTPN11, SOS1, SOS2, RAF1, RIT1, RRAS2 Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for Noonan syndrome KFV genetic testing when the following criteria met:

• Pre- and post-test genetic counseling; AND
• For reproductive decision-making when the individual to be tested is of reproductive age and has an affected first-degree relative with a pathogenic or likely pathogenic variant in the KRAS, LZTR1, MRAS, NRAS, PTPN11, SOS1, SOS2, RAF1, RIT1, RRAS2 gene (test KFV).

NOONAN SYNDROME WITH MULTIPLE LENTIGINES

Noonan Syndrome with Multiple Lentigines (PTPN11 Gene) – Affected Individual

Humana members may be eligible under the Plan for PTPN11 gene testing to confirm a diagnosis of Noonan syndrome with multiple lentigines when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested exhibits at least 1 distinctive facial feature (high forehead, ptosis, widely-spaced eyes that are downslanting, strikingly blue irides, neck webbing, low-set posteriorly rotated ears); AND

Genetic Testing for RASopathy Syndromes Effective Date: 09/28/2023 Revision Date : 09/28/2023 Review Date : 09/28/2023 Policy Number: HUM-0565-003 Page: 10 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Multiple lentigines; AND
1. Congenital heart defects (eg, atrial septal defect, hypertrophic cardiomyopathy, pulmonary stenosis); OR
2. Cryptorchidism; OR
3. First-degree relative diagnosed with or features suggestive of Noonan syndrome; OR
4. Lymphatic dysplasia; OR
5. Mild developmental delay; OR
6. Pectus carinatum/excavatum; OR
7. Short stature below 10th percentile

Noonan Syndrome with Multiple Lentigines – PTPN11 Known Familial Pathogenic or Likely Pathogenic Variant

Humana members may be eligible under the Plan for Noonan syndrome with multiple lentigines KFV genetic testing when the following criteria are met:

• Pre- and post-test genetic counseling; AND
• Individual to be tested has an affected first-degree relative with a pathogenic or likely pathogenic variant in the PTPN11 gene (test KFV)

Coverage Limitations

Humana members may NOT be eligible under the Plan for genetic testing for RASopathy syndrome for any of the following:

• Individual to be tested has an affected first-, second- or third-degree relative with a negative genetic testing result for the associated condition
• KFV detection analysis using either of the following methods:

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Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Multigene panel that includes the KFV
• Sequencing, deletion/duplication analysis or large genomic rearrangement analysis (conducted individually, as comprehensive testing or sequentially) without KFV results of a first, second- or third-degree relative
• Deletion/duplication information is obtained as part of the sequencing procedure but submitted as an independent analysis

These are considered not medically necessary as defined in the member’s individual certificate. Please refer to the member’s individual certificate for the specific definition.

Humana members may NOT be eligible under the Plan for genetic testing for RASopathy syndrome for any indications, genes or tests other than those listed above including, but may not be limited to:

• Cardiofaciocutaneous syndrome single gene testing for any gene other than those listed above including, but not limited to:
  • NRAS
  • PTPN11
  • RAF1
  • SHOC2
  • SOS1
• CBL gene single gene testing for any RASopathy syndrome
• Costello syndrome single gene testing for any gene other than those listed above including, but not limited to:
  • KRAS
  • MAP2K1
  • NRAS
  • PTPN11
  • RAF1
  • SHOC2

Genetic Testing for RASopathy Syndromes Effective Date: 09/28/2023 Revision Date : 09/28/2023 Review Date : 09/28/2023 Policy Number: HUM-0565-003 Page: 12 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Noonan syndrome single gene testing for any gene other than those listed above including, but may not be limited to:
• A2ML1
• MAP2K1
• MAP2K2
• RASA1
• RASA2
• RRAS
• SHOC2
• Noonan syndrome with multiple lentigines single gene testing for any gene other than those listed above including, but may not be limited to:
• MAP2K1
• NRAS
• RAF1
• Large multigene panels (analysis of more than 12 genes) for the following indications:
• Cardiofaciocutaneous syndrome
• Noonan syndrome
• Noonan syndrome with multiple lentigines
• Targeted multigene panels (analysis of 12 or fewer genes) that do not include the core genes listed above

These are considered experimental/investigational as they are not identified as widely used and generally accepted for any other proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Genetic Testing for RASopathy Syndromes Effective Date: 09/28/2023 Revision Date : 09/28/2023 Review Date : 09/28/2023 Policy Number: HUM-0565-003 Page: 13 of 23

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Additional information about RASopathy syndromes may be found from the following websites:

Background

• National Library of Medicine

Medical Alternatives

Physician consultation is advised to make an informed decision based on an individual’s health needs.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.