This document addresses several tests including:

• Gene panel testing (for the purposes of this document, a gene panel is defined by five or more genes or gene variants tested on the same day on the same member by the same rendering provider)
  • This includes use of circulating tumor DNA panel testing (liquid biopsy), for example, as an alternative to tissue biopsy in the diagnosis of cancer, for clinical response to targeted agents of cancer treatment, for early cancer detection (that is, screening) and/or for cancer surveillance.
• Whole genome sequencing
• Whole exome sequencing
• Molecular profiling (also called comprehensive genomic profiling), including use of circulating tumor DNA panel tests (liquid biopsy) for solid tumors
• Polygenic risk score testing
• Chromosome conformation signatures

Note: This document does not address tests that include 4 or fewer genes or gene mutation variants. Please refer to:

• CG-GENE-13 Genetic Testing for Inherited Diseases
• CG-GENE-14 Gene Mutation Testing for Cancer Susceptibility and Management

Note: This document does not address circulating tumor cell (CTC) testing. Please refer to:

• LAB.00015 Detection of Circulating Tumor Cells

Note: Please see the following related documents for additional information:

• CG-GENE-10 Chromosomal Microarray Analysis (CMA) for Developmental Delay, Autism Spectrum Disorder, Intellectual Disability and Congenital Anomalies
• CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis
• CG-GENE-16 BRCA Genetic Testing
• CG-GENE-19 Measurable Residual Disease Assessment in Lymphoid Cancers Using Next Generation Sequencing
• GENE.00010 Panel and other Multi-Gene Testing for Polymorphisms to Determine Drug-Metabolizer Status

Position Statement

Medically Necessary:

Gene Panel Testing for Inherited Diseases

Gene panel testing for inherited diseases is considered medically necessary when criteria A or B below are met:

1. Hereditary retinal disorders:
   1. Individual has suspected inherited retinal degenerative disease; and
   2. Results of the panel are likely to guide treatment decisions.
2. Ashkenazi Jewish associated inherited disorders (both criteria 1 and 2):
   1. Either criteria a or b:
      1. Individual has suspected genetic disease associated with Ashkenazi Jewish descent; or
      2. As part of preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status when the parent or prospective parent is of Ashkenazi Jewish descent; and
   2. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention, and resources; and
      3. Counseling to promote informed choices and adaption to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.

Gene Panel Testing for Cancer Susceptibility

Gene panel testing for cancer susceptibility is considered medically necessary when criteria A or B below are met:

1. Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer [HNPCC]):
   1. When the panel contains, at a minimum, the following genes: EPCAM, MLH1, MSH2, MSH6, and PMS2; and
   2. Individual meets criteria for Lynch Syndrome genetic testing according to CG-GENE-15.
2. Breast Cancer Susceptibility:
   1. When the panel contains, at a minimum, the following genes: ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D; and
   2. Individual meets criteria for BRCA genetic testing according to CG-GENE-16.

Gene Panel Testing for Cancer Management

Gene panel testing for cancer management is considered medically necessary when criteria A, B, C, D. E, or F below are met:

1. Prostate Cancer:
   1. The panel evaluates homologous recombination repair (HRR) gene alterations; and
   2. The individual is a candidate for treatment using a poly (ADP-ribose) polymerase (PARP) inhibitor.
2. Advanced Non-Small Cell Lung Cancer:
   1. Prior to initiating first-line therapy; and
   2. When the panel contains, at a minimum, the following genes (mutations, rearrangements, fusions, or amplifications): ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET, and ROS1.
3. Myelodysplastic Syndromes (MDS):
   1. For initial evaluation of MDS; and
   2. When the panel contains, at a minimum, the following genes: ASXL1, DNMT3A, EZH2, NRAS, RUNX1, SF3B1, SRSF2, STAG2, TET2, TP53, U2AF1, ZRSR2.
4. Acute Myeloid Leukemia (AML):
   1. For initial evaluation of newly diagnosed or relapsed AML; and
   2. When the panel contains, at a minimum, the following genes: ASXL1, BCR-ABL, c-KIT, CEBPA (biallelic), FLT3-ITD, FLT3-TKD, IDH1, IDH2, NPM1, PML-RAR alpha, RUNX1, and TP53.
5. Acute Lymphoblastic Leukemia (ALL):
   1. For initial evaluation of ALL; and
   2. When the panel contains, at a minimum, the following genes: ABL1, ABL2, CRLF2, CSF1R, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, and SH2B3.
6. In Vitro Companion Diagnostic Device (IVD)
   1. When the test is an IVD and is used in accordance with the U.S. Food and Drug Administration (FDA) labeled indication.
      Link to the up-to-date list of FDA cleared or approved Companion Diagnostic Devices:
      https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools

Circulating Tumor DNA (ctDNA) Panel Testing
Use of a ctDNA panel test is considered medically necessary when criteria A, B, or C below are met:

1. Prostate Cancer:
   1. The panel evaluates HRR gene alterations; and
   2. The individual is a candidate for treatment using a PARP inhibitor; and
   3. Formalin-fixed paraffin-embedded tumor tissue (FFPET) is inadequate in quality or quantity or is unavailable for testing.
2. Advanced Non-Small Cell Lung Cancer:
   1. Prior to initiating first-line therapy; and
   2. When the panel contains, at minimum, the following genes (mutations, rearrangements, fusions, or amplifications): ALK, BRAF, EGFR, ERBB2 (HER2), KRAS, MET, NTRK, RET, and ROS1; and
   3. FFPET tissue is inadequate in quality or quantity or is unavailable for testing.
3. In Vitro Companion Diagnostic Device (IVD)
   1. When the test is an IVD and is used in accordance with the U.S. Food and Drug Administration (FDA) labeled indication.
      Link to the up-to-date list of FDA cleared or approved Companion Diagnostic Devices:
      https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools

Whole Exome Sequencing (WES)

Whole exome sequencing is considered medically necessary in the evaluation of an individual who meets all of the following criteria A, B, and C:

1. Meets one of the following criteria:
   1. Multiple anomalies not specific to a well-delineated genetic syndrome apparent before 1 year of age; or
   2. Apparently non-syndromic developmental delay/intellectual disability with onset prior to 18 years of age; or
   3. For the evaluation of a live fetus with abnormal fetal anatomic findings which are characteristic of a genetic abnormality; and
2. When the results of testing would confirm or establish a clinical diagnosis that may lead to changes in management; and
3. Genetic counseling, which encompasses all of the following components, has been performed:
   1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
   2. Education about inheritance, genetic testing, disease management, prevention and resources; and
   3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
   4. Counseling for the psychological aspects of genetic testing.

Note: WES may include comparator WES testing of the biologic parents or sibling of the affected individual.

Molecular Profiling for the Evaluation of Malignancies

Molecular profiling is considered medically necessary when all of the criteria below are met:

1. The individual has an unresectable or metastatic solid tumor; and
2. The test is used to assess tumor mutation burden (TMB); and
3. The test is used to identify candidates for checkpoint inhibition immunotherapy; and
4. The individual has no satisfactory alternative treatment options.

Molecular Profiling using a circulating tumor (ctDNA) test is considered medically necessary when all of the criteria below are met:

1. The individual has an unresectable or metastatic solid tumor; and
2. The test is used to assess TMB; and
3. The test is used to identify candidates for checkpoint inhibition immunotherapy; and
4. The individual has no satisfactory alternative treatment options; and
5. FFPET tissue is inadequate in quality or quantity or is unavailable for testing.

Not Medically Necessary:

Testing using gene panels is considered not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Testing using circulating tumor DNA panels is considered not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Testing using whole exome sequencing is considered not medically necessary for all other indications, including when the medically necessary criteria above have not been met, and for repeat sequencing.

Investigational and Not Medically Necessary:

Whole genome sequencing is considered investigational and not medically necessary for all indications.

Molecular profiling is considered investigational and not medically necessary for all other indications, including when the medically necessary criteria above have not been met.

Polygenic risk score testing is considered investigational and not medically necessary for all indications.

Chromosome conformation signature testing is considered investigational and not medically necessary for all indications.