BlueCross BlueShield of Tennessee Medical Policy Manual

Whole Exome and Genome Sequencing

Does Not Apply to Commercial Genetic Testing Program effective 6/1/2018


Whole exome sequencing (WES) analyses the portion of the genome that contains protein-coding DNA, known as exons; whole genome sequencing (WGS) analyses both coding and noncoding regions of the genome. WES and WGS have been proposed for use in children presenting with disorders and anomalies that have not been explained by standard clinical workup.  While exons represent only about 2% of the genome, they account for approximately 85% of disease-causing genetic variants.

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders. Experts recommend formal genetic counseling when genetic testing for an inherited condition is considered.





There are no regulations required by the U.S. Food and Drug Administration (FDA) for genetic testing. Laboratories performing clinical tests must be certified for high complexity testing under the Clinical Laboratory Improvement Amendments (CLIA) of 1988.

Published evidence of well-designed studies in peer review journals is insufficient to determine whether the use of whole genome sequencing tests improve health outcomes.


American College of Medical Genetics and Genomics. (2012). Policy statement. Points to consider in the clinical application of genomic sequencing. Retrieved May 14, 2013 from

American College of Medical Genetics and Genomics. (2014, September). ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Retrieved June 29, 2017 from 

American College of Medical Genetics and Genomics. (2017, February). Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Retrieved June 29, 2017 from

BlueCross BlueShield Association. Medical Policy Reference Manual. (10:2017). Whole exome and whole genome sequencing for diagnosis of genetic disorders (2.04.102). Retrieved June 29, 2017 from BlueWeb. (33 articles and/or guidelines reviewed)

Monroe, G., Frederix, G., Savelberg, S., de Vries, T., Duran, K., van der Smagt, J., et. al., (2016, September) Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genetic Medicine. 18(9):949-56. Abstract retrieved July 5, 2017 from PubMed database.

Montenegro, G., Powell, E., Huang, J., Speziani, F., Edwards, Y., Beecham, G., et al. (2011). Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Annals of Neurology, 69 (3), 464-470. (Level 4 evidence)

Need, A. C., Shashi, V., Hitomi, Y., Schoch, K. V., McDonald, M. T., et al. (2012). Clinical application of exome sequencing in undiagnosed genetic conditions. Journal of Medical Genetics, 49 (6), 353-361. (Level 4 evidence)

Nguyen, M., and Charlebois, K. (2015, October) The clinical utility of whole-exome sequencing in the context of rare diseases - the changing tides of medical practice. Clinical Genetics. 88(4):313-9. Abstract retrieved July 5, 2017 from PubMed database.

Nolan, D., and Carlson, M. (2016, June) Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. Journal of Child Neurology. 31(7): 887-94. Abstract retrieved July 5, 2017 from PubMed database.

Rosell, A., Pena, L., Schoch, K., Spillmann, R., Sullivan, J., Hooper, S., et. al. (2016, October) Not the end of the odyssey: parental perceptions of whole exome sequencing (WES) in pediatric undiagnosed disorders. Journal of Genetic Counseling. 25(5):1019-31. Abstract retrieved July 5, 2017 from PubMed database.

Rump, P., Omid, J., van Dijk-Bos, K., Lennart, F.,  Johansson, A.,  van Essen, A., Verjeij, J., et. al., (2016) Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. BMC Medical Genomics. (2016)9:7. (Level 4 evidence)

Sener, E. F., Canatan, H., & Ozkul, Y. (2016). Recent advances in autism spectrum disorders: applications of whole exome sequencing technology. Psychiatry Investigation, 13 (3), 255-264. (Level 2 evidence)

Stark, Z., Tan, T., Chong, B., Brett, G., Yap, P., Walsh, M., et. al., (2016, November) A prospective evaluation of whole-exome sequencing as a first tier molecular test in infants with suspected monogenic disorders. Genetic Medicine. 18(1):1090-1096. Abstract retrieved July 5, 2017 from PubMed database.

Technology Evaluation Center. (2013, August). Special report: Exome sequencing for clinical diagnosis of patients with suspected genetic disorders (Vol. 28, No. 3). Chicago: BlueCross BlueShield Association. (61 articles and/or guidelines reviewed)

Thevenon, J., Duffourd, Y., Masurel-Paulet, A., Lefebvre, M., Feillet, F., El Chehadeh-Djebbar, S., et. al. (2016, June) Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clinical Genetics. 89(6):700-7. Abstract retrieved July 5, 2017 from PubMed database.

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Indication. (2016, September). Whole genome sequencing fin neonatal and pediatric patients. Retrieved June 29, 2017 from  (27 articles and/or guidelines reviewed)

Winifred S. Hayes, Inc. Genetic Test Evaluation (GTE) Report. (2013, August; last update search August 2014). Whole exome sequencing for noncancer indications. Retrieved May 11, 2015 from  (44 articles and/or guidelines reviewed)

Yu, Y., Wu, B. L., Wu, J., & Shen, Y. (2012). Exome and whole-genome sequencing as clinical tests: A transformative practice in molecular diagnostics. Clinical Chemistry, 58 (11), 1507-1509. (Level 2 evidence)




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