Description of Procedure or Service

Definitions

Genetic testing refers to the use of technologies that identify genetic variation, which include genomic, transcriptional, proteomic, and epigenetic alterations, for the prevention, diagnosis, and treatment of disease (Li et al., 2017; Raby, 2018).

Somatic variations or mutations are defined as a genetic alteration that occurs after conception in any of the cells of the body, except the germ cells, and therefore are not passed on to offspring (Li et al., 2017).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for general genetic testing for somatic disorders when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When General Genetic Testing, Somatic Disorders is covered

1. General testing for a specific genetic mutation or mutations that have documented clinical utility is considered medically necessary for diagnosis, selection of therapy, or prognostication when there is a documented benefit based on the presence of such mutations in the tumor, or neoplastic hematologic cells.
2. Repeat testing is considered medically necessary for recurrence monitoring, OR
3. Repeat testing is considered medically necessary when there is the possibility of further genetic alterations in the hematologic malignancy, primary tumor or metastasis AND knowledge of these changes would result in the addition, elimination or alteration of non-investigational therapies.

When General Genetic Testing, Somatic Disorders is not covered

Testing with a gene panel containing genes that do not meet the criteria in item 1 above is considered investigational.

Policy Guidelines

Background

Advancements in technology and availability of sequencing, previously constrained by limitations of sequential single-gene testing on limited patient samples, have led to significant strides in our understanding of the genetic basis of inherited and somatic conditions. Variants detected by genetic testing include inherited germline variants and somatic mutations (Konnick & Pritchard, 2016).

Spontaneous mutations accumulate in somatic cells over a lifetime. While the majority of these mutations are inconsequential, others alter key cellular functions (Martincorena & Campbell, 2015). Genetic variations may be activating, resulting in a gain of function or loss of regulation of a protein, or inactivating, such as nonsense, splice-site, and frameshift insertion/deletion mutations, thereby causing a loss of function. They can range from single-nucleotide variants (SNVs) that cause a missense, silent, or nonsense amino acid substitution, or a splice site alteration affecting normal splicing of the mRNA transcript, to one or more nucleotides involved in duplications, deletions, insertions, or even a more complex pattern (Li et al., 2017). Also common is a change in copy number, as well as structural rearrangements, including chromosome translocations, deletions, duplication, or inversions (Li et al., 2017).

Early somatic mutations can cause developmental disorders, whereas the progressive accumulation of mutations throughout life can lead to cancer and contribute to aging (Martincorena & Campbell, 2015). Molecular profiles of tumors have been found to have clinical utility in guiding the clinical management of cancer patients, providing diagnostic or prognostic information, or identifying a potential treatment regimen or targeted therapy(Li et al., 2017). Increasingly, somatic mutations are being identified in diseases other than cancer, including neurodevelopmental diseases (Poduri, Evrony, Cai, & Walsh, 2013).

Applicable Federal Regulations

N/A

Guidelines and Recommendations

Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists

The Joint Commission recommended that somatic variants be categorized by and reported based on their impact on clinical care as follows(Li et al., 2017):

“Somatic variants include SNVs, indels, fusion genes resulting from genomic rearrangements, and CNVs. Unlike interpretation of germline sequence variations, which focuses on pathogenicity of a variant for a specific disease or disease causality, interpretation of somatic variants should be focused on their impact on clinical care. A variant can be considered a biomarker that affects clinical care if it predicts sensitivity, resistance, or toxicity to a specific therapy, alters the function of the gene, which can be targeted by approved or investigational drugs, serves as an inclusion criterion for clinical trials, influences disease prognosis, assists in establishing a diagnosis of a cancer, or warrants implementing surveillance measures for early cancer detection. Clinical impacts should, therefore, include therapeutic, prognostic, diagnostic, and preventive actions. The clinical impact of a given variant should be determined according to currently available evidence. Evidence used for variant categorization can be weighed differently based on its significance in clinical decision making. On the basis of literature review and Working Group consensus, we propose to group clinical and experimental evidence into four levels:

1. Level A, biomarkers that predict response or resistance to US FDA-approved therapies for a specific type of tumor or have been included in professional guidelines as therapeutic, diagnostic, and/or prognostic biomarkers for specific types of tumors;
2. Level B, biomarkers that predict response or resistance to a therapy based on well-powered studies with consensus from experts in the field, or have diagnostic and/or prognostic significance of certain diseases based on well-powered studies with expert consensus;
3. Level C, biomarkers that predict response or resistance to therapies approved by FDA or professional societies for a different tumor type (ie, off-label use of a drug), serve as inclusion criteria for clinical trials, or have diagnostic and/or prognostic significance based on the results of multiple small studies;
4. Level D, biomarkers that show plausible therapeutic significance based on preclinical studies, or may assist disease diagnosis and/or prognosis themselves or along with other biomarkers based on small studies or multiple case reports with no consensus.”

NCCN Guidelines

Multiple somatic mutations have been incorporated into the diagnostic workups recommended by the NCCN. Furthermore, the NCCN has several guidelines which recommend that gene expression profiling, or multiple gene testing may be helpful, more efficient and/or cost-effective for selected patients (NCCN, 2017). Please see “Related Policies”.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81175, 81176, 81261, 81262, 81263, 81264, 81265, 81266, 81315, 81316, 81340, 81341, 81342, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 81400, 81401, 81402, 81403, 81405, 81479, 81599, 88237, 88239, 88240, 88241, 88269, 88271, 88272, 88273, 88274, 88275, 88280, 88283, 88285, 88289, 88291, 88299, 96040, G0452, S0265

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Konnick, E. Q., & Pritchard, C. C. (2016). Germline, hematopoietic, mosaic, and somatic variation: interplay between inherited and acquired genetic alterations in disease assessment. Genome Med, 8(1), 100. doi:10.1186/s13073-016-0350-8

Li, M. M., Datto, M., Duncavage, E. J., Kulkarni, S., Lindeman, N. I., Roy, S., Nikiforova, M. N. (2017). Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn, 19(1), 4-23. doi:10.1016/j.jmoldx.2016.10.002

Martincorena, I., & Campbell, P. J. (2015). Somatic mutation in cancer and normal cells. Science, 349(6255), 1483-1489. doi:10.1126/science.aab4082

NCCN. (2017). NCCN Clinical Practice Guidelines in Oncology. NCCN Clinical Practice Guidelines in Oncology. Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013). Somatic Mutation, Genomic Variation, and Neurological Disease. Science, 341(6141), 1237758. doi:10.1126/science.1237758

Raby, B. (2018). Personalized medicine - UpToDate. In J. Tirnauer (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/personalized-medicine?source=see_link.

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for general genetic testing for somatic disorders when it is determined to be medically necessary because the medical criteria and guidelines are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)