MOLECULAR PATHOLOGY/MOLECULAR DIAGNOSTICS/ GENETIC TESTING

Transcription

1 UnitedHealthcare Medicare Advantage Policy Guideline MOLECULAR PATHOLOGY/MOLECULAR DIAGNOSTICS/ GENETIC TESTING Guideline Number: MPG Approval Date: July 11, 2018 Table of Contents Page TERMS AND CONDITIONS... 1 PURPOSE... 1 POLICY SUMMARY... 2 APPLICABLE CODES... 6 REFERENCES GUIDELINE HISTORY/REVISION INFORMATION Related Medicare Advantage Policy Guidelines Clinical Diagnostic Laboratory Services Corus CAD (Coronary Artery Disease) Related Medicare Advantage Coverage Summaries Genetic Testing Laboratory Tests and Services TERMS AND CONDITIONS The Medicare Advantage Policy Guidelines are applicable to UnitedHealthcare Medicare Advantage Plans offered by UnitedHealthcare and its affiliates. These Policy Guidelines are provided for informational purposes, and do not constitute medical advice. Treating physicians and healthcare providers are solely responsible for determining what care to provide to their patients. Members should always consult their physician before making any decisions about medical care. Benefit coverage for health services is determined by the member specific benefit plan document* and applicable laws that may require coverage for a specific service. The member specific benefit plan document identifies which services are covered, which are excluded, and which are subject to limitations. In the event of a conflict, the member specific benefit plan document supersedes the Medicare Advantage Policy Guidelines. Medicare Advantage Policy Guidelines are developed as needed, are regularly reviewed and updated, and are subject to change. They represent a portion of the resources used to support UnitedHealthcare coverage decision making. UnitedHealthcare may modify these Policy Guidelines at any time by publishing a new version of the policy on this website. Medicare source materials used to develop these guidelines include, but are not limited to, CMS National Coverage Determinations (NCDs), Local Coverage Determinations (LCDs), Medicare Benefit Policy Manual, Medicare Claims Processing Manual, Medicare Program Integrity Manual, Medicare Managed Care Manual, etc. The information presented in the Medicare Advantage Policy Guidelines is believed to be accurate and current as of the date of publication, and is provided on an "AS IS" basis. Where there is a conflict between this document and Medicare source materials, the Medicare source materials will apply. You are responsible for submission of accurate claims. Medicare Advantage Policy Guidelines are intended to ensure that coverage decisions are made accurately based on the code or codes that correctly describe the health care services provided. UnitedHealthcare Medicare Advantage Policy Guidelines use Current Procedural Terminology (CPT **), Centers for Medicare and Medicaid Services (CMS), or other coding guidelines. References to CPT or other sources are for definitional purposes only and do not imply any right to reimbursement or guarantee claims payment. Medicare Advantage Policy Guidelines are the property of UnitedHealthcare. Unauthorized copying, use and distribution of this information are strictly prohibited. *For more information on a specific member's benefit coverage, please call the customer service number on the back of the member ID card or refer to the Administrative Guide. **CPT is a registered trademark of the American Medical Association. PURPOSE The Medicare Advantage Policy Guideline documents are generally used to support UnitedHealthcare Medicare Advantage claims processing activities and facilitate providers submission of accurate claims for the specified services. The document can be used as a guide to help determine applicable: Medicare coding or billing requirements, and/or Medical necessity coverage guidelines; including documentation requirements. Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 1 of 19

2 UnitedHealthcare follows Medicare guidelines such as LCDs, NCDs, and other Medicare manuals for the purposes of determining coverage. It is expected providers retain or have access to appropriate documentation when requested to support coverage. Please utilize the links in the References section below to view the Medicare source materials used to develop this resource document. This document is not a replacement for the Medicare source materials that outline Medicare coverage requirements. Where there is a conflict between this document and Medicare source materials, the Medicare source materials will apply. POLICY SUMMARY Overview This policy overview addresses molecular and genetic tests that have proven efficacy in the diagnosis or treatment of medical conditions. Hereditary Breast and Ovarian Cancer Anomalies in two genes, BRCA1 and BRCA2, are associated with an increased risk of breast and ovarian cancer. Alterations in BRCA1 and BRCA2 explain many, but not all, of inherited forms of breast and ovarian cancer. With the identification of BRCA1 and BRCA2, it is now possible to test for abnormalities in the genes to provide information on the future risk of cancer and to make important treatment decisions in affected individuals. Approximately five- to ten-percent of all breast cancers, and a similarly small percentage of ovarian cancers, are attributed to dominantly inherited susceptibility. (See LCDs for Cancer section for specific coverage guidelines.) Oncotype Assays for Breast Cancer Oncotype DX TM is a gene panel test developed for node-negative, estrogen receptor (ER)-positive breast cancer. This test is employed to identify breast cancer patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy. Oncotype DX DCIS assay is for breast cancer patients diagnosed with ductal carcinoma in situ (DCIS) who are planning on having breast conserving surgery and considering adjuvant radiation therapy. (See LCDs for Cancer section for specific coverage guidelines) Management of Breast Cancer Treatment MammaPrint is an FDA cleared in vitro microarray diagnostic test that uses gene expression profiling to analyze the gene activity of the tumor itself. MammaPrint enables a more accurate prognosis of breast cancer recurrence to assist physicians in dealing with their patients with breast cancer. (See LCDs for Cancer section for specific coverage guidelines.) The Breast Cancer Index (BCI) Genetic Assay uses pathologic complete response to interrogate selected proliferationrelated and endocrine signaling-related genes, and may identify a subset of postmenopausal women who are at increased risk of late relapses for estrogen receptor positive breast cancer and who may derive a greater benefit from extended hormone therapy. (See LCDs for Cancer section for specific coverage guidelines.) The EndoPredict breast cancer gene expression test is for the management of post-menopausal women diagnosed with early-stage (TNM stage T1-3, N0-1) estrogen-receptor (ER) positive, Her2-negative breast cancer, who are either lymph node-negative or who have 1-3 positive nodes, and for whom treatment with adjuvant endocrine therapy (e.g., tamoxifen or aromatase inhibitors) is being considered. The test is used by physicians in the management of these patients by identifying those who have sufficiently low risk of distant recurrence (DR) at 10 years and may safely forego chemotherapy. (See LCDs for Cancer section for specific coverage guidelines.) Prosigna Breast Cancer Prognostic Gene Signature Assay is used for the management of females with breast cancer who have undergone surgery in conjunction with locoregional treatment. A risk category and score are generated to assess risk of DR of breast cancer. (See LCDs for Cancer section for specific coverage guidelines.) Hereditary Colorectal and Endometrial Cancer Syndromes Lynch Syndrome (previously denoted as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome), is an autosomal dominant syndrome that accounts for about 3-5% of colorectal cancer cases. HNPCC syndrome mutations occur in the following genes: hmlh1, hmsh2, hmsh6, PMS2 and EPCAM. Colorectal cancers associated with Lynch syndrome occur at a younger age (average age of onset between years of age) compared with the more common colorectal cancers typically found during the seventh decade of life. Gynecologic cancers may precede colorectal cancer in as many as 50% of female HNPCC gene mutation carriers. Familial Adenomatous Polyposis (FAP) is an autosomal dominant syndrome caused by a germ-line mutation of the APC gene. Characteristically, affected patients develop multiple adenomas diffusely throughout the colon beginning in their teens. Colorectal cancer is inevitable in patients with FAP if colectomy is not performed. Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 2 of 19

3 MYH-associated polyposis (MAP) is an autosomal recessive syndrome linked to germ-line mutations of the MYH gene. The full clinical picture of MYH-associated polyposis (MAP) is incompletely understood at this time. Current evidence suggests it is associated with about % of colorectal cancers. (See LCDs for Cancer section for specific coverage guidelines) Therapy-Directing Testing Coverage for KRAS testing is limited to use in patients with metastatic colorectal cancer for whom either cetuximab (Erbitux) or panitumumab (Vectibix) therapy is contemplated as being appropriate. Coverage for JAK2 testing is appropriate in patients with signs or symptoms suggesting an underlying chronic myeloproliferative disorder, including increased red-cell mass, increased platelets, unexplained persistent peripheral cytopenia to cytosis, unexplained peripheral or hepatic vein thrombosis (Budd-Chiari Syndrome) or bone marrow examination showing features of a chronic myeloproliferative disorder. Documentation must also indicate that the provider anticipates that the test result is likely to be of use in management of the condition. The BCR/ABL fusion gene is the classic mutation seen in Chronic Myelogenous Leukemia (CML) and is also seen in Acute Lymphocytic Leukemia (ALL) and certain other hematologic diseases. Major factors influencing consideration of testing for this gene include some that are too non-specific to support coverage. (See LCDs for Cancer section for specific coverage guidelines) Multiple Myeloma Gene Expression Profile MyPRS is a test for Multiple Myeloma Gene Expression Profile. Multiple myeloma is an incurable malignancy of terminally differentiated antibody secreting plasma cells. The median overall survival is reported at 3-4 years. Disease sequelae associated with this malignancy includes anemia, immunodeficiency, renal insufficiency/failure, lytic bone lesions and hypercalcemia. This test is used only after an initial diagnosis of multiple myeloma has been made and will be available to be used in stratification of therapeutic interventions. The coverage is set to include only two clinical settings: Once after initial diagnosis is made, or If relapse has occurred and a change in the therapeutic modalities is contemplated (See LCDs in Cancer section for coverage guidelines.) Loss-of-Heterozygosity Based Topographic Genotyping with PathfinderTG /PancraGEN TM Test for Pancreatic Cyst/Mass Combining pathologic study with molecular analyses of microdissected tissue, is claimed to enhance the ability to provide more specific diagnostic information, to help guide treatment decisions. These testing combinations are generally known as topographic genotyping. (See LCD Miscellaneous section for coverage guidelines.) Circulating Tumor Cell (CTC) Assay CTCs represent the point in the metastatic process of solid tumors when cells from a primary tumor invade, detach, disseminate, colonize and proliferate in a distant site. Detection of elevated CTCs during therapy may be an accurate indication of subsequent rapid disease progression and mortality in breast, colorectal and prostate cancer, noting that FDA labeling includes each of these neoplasms. As a result of limited acceptable study data, CTCs are considered not medically necessary, for all indications. (See LCDs for CTCs for specific coverage guidelines) NRAS Genetic Testing of Tumor Tissue This is genetic testing of tumor tissue for somatic mutations in the NRAS gene. RAS oncogene is a superfamily of signal transduction proteins, which are proteins that communicate signals between the cells. DNA mutations in the RAS family genes turn the signals on permanently such that the cells divide nonstop, leading to cancer. (See LCDs in Cancer section for coverage guidelines.) Bladder Tumor Markers Cystoscopy in conjunction with bladder tumor markers is the standard practice to evaluate patients with symptoms suggesting bladder cancer and to monitor treated patients for recurrence or progression. Urinary cytology has close to a 90%-100% specificity, but only 10%-50% sensitivity for low grade urinary cancer (UC) detection. Due to this deficit, clinicians have sought noninvasive tumor markers detectable in urine. Bladder Tumor Marker tests include: BTA TRAK, Nuclear matrix protein 22 (NMP-22), NMP-22 BladderChek, The UroVysion, BTA (bladder tumor antigen) stat, and The ImmunoCyt. (See LCDs for Cancer section for coverage guidelines.) NSCLC (non-small cell lung cancer), Comprehensive Genomic Profile Testing This test is a comprehensive somatic genomic profiling on tumor tissue-only (hereafter called CGP) for patients with metastatic non-small cell lung cancer (NSCLC) who are lifetime non-smokers (also known as never-smokers) or Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 3 of 19

4 former light smokers ( 15 pack year history) and who tested negative for epidermal growth factor receptor (EGFR) mutations, EML4-ALK rearrangements, and ROS1 rearrangements when initial testing was done by an FDA-approved companion diagnostic (CDx) or by a laboratory developed test (LDT) for these genomic alterations. (See LCDs for Cancer section for coverage guidelines.) Molecular Assays for Prostate Cancer ConfirmMDx is associated with prostate cancer. ConfirmMDx is intended for use in patients with high-risk factors such as elevated/rising prostate-specific antigen (PSA) or abnormal digital rectal examination (DRE), with a negative or non-malignant abnormal histopathology finding (e.g., atypical cell or high grade prostate intraepithelial neoplasia (HGPIN)) in the previous biopsy, and is being considered for repeat biopsy. (See LCDs for Cancer section for coverage guidelines.) The PROGENSA PCA3 Assay and ProMark Risk Score are automated molecular tests (assay) that help physicians determine the need for prostate biopsies in men. (See LCDs for Cancer section for coverage guidelines.) Oncotype DX Prostate Cancer is used to determine which patients with early stage, needle biopsy proven prostate cancer, can be conservatively managed rather than treated with definitive surgery or radiation therapy. (See LCDs for Cancer section for coverage guidelines.) Prolaris is an RNA based assay measuring the expression of 31 cell cycle progression (CCP) genes and 15 genes that act as internal controls and normalization standards in each patient sample. The assay results are reported as a numerical score along with accompanying interpretive information. (See LCDs for Cancer section for coverage guidelines.) The Decipher prostate cancer assay, a 22-biomarker expression signature using oligonucleotide microarray technology, interrogates 1.4 million RNAs extracted from the radical prostectomy specimen. The biomarkers that comprise the Decipher classifier include cell cycle progression, androgen signaling, cell adhesion, tumor cell motility, migration and immune evasion functions. (See LCDs for Cancer for coverage guidelines.) AlloMap for Heart Transplant Recipients AlloMap Molecular Expression Testing is a non-invasive gene expression test used to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection at the time of testing in conjunction with standard clinical assessment. AlloMap testing measures the expression levels of 20 genes from a blood sample. The combined expression of these genes is represented as an AlloMap test score. (See LCDs for Molecular Pathology section for coverage guidelines.) Molecular Pathology Procedures for Human Leukocyte Antigen (HLA) Typing Human Leukocyte Antigen (HLA) typing is performed to assess compatibility of recipients and potential donors as a part of solid organ and hematopoietic stem cell/ bone marrow pretransplant testing. HLA testing is also performed to identify HLA alleles and allele groups (antigen equivalents) associated with specific diseases and individualized responses to drug therapy (e.g., HLA-B*27 and ankylosing spondylitis; HLA-B57:01 and abacavir hypersensitivity; HLA-B*15:02 and carbamazepine, phenytoin or fosphenytoin hypersensitivity), as well as other clinical uses. One or more HLA genes may be tested in specific clinical situations (e.g., HLA A, B, C,-DRB1, and DQB1 for kidney transplantation). Each HLA gene typically has multiple variant alleles or allele groups that can be identified by typing. (See LCDs for Molecular Pathology for coverage guidelines.) GeneSight Assay for Refractory Depression GeneSight Psychotropic is a multiplex pharmacogenomic test involving the analysis of fifty alleles (SNPs) from six different genes. The test results in the differentiation of psychoactive drugs that are likely to be effective and welltolerated by a particular patient versus those that are not. GeneSight testing may only be ordered by licensed psychiatrists contemplating an alteration in neuropsychiatric medication for patients diagnosed with major depressive disorder (MDD) after at least one prior neuropsychiatric medication failure. (See LCD for GeneSight in Miscellaneous section for coverage guidelines.) CYP2C19, CYP2D6, CYP2C9, and VKORC1 Genetic Testing for Drug Metabolism Genetic alterations or polymorphisms are common in these drug metabolizing enzymes. These polymorphisms can lead to differences in individual drug response secondary to variation in metabolism. Pharmacogenetic testing has been proposed to predict individual response to a variety of drugs. In certain scenarios, an individual patient may benefit from this genetic testing in determining dosage and likely response to specific medications. (See LCDs for Drug Metabolism in Miscellaneous section for coverage guidelines.) Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 4 of 19

5 Assays for Rheumatoid Arthritis The Avise PG Assay, developed to support dose optimization and therapeutic decision making for patients diagnosed with rheumatoid arthritis (RA) on methotrexate ('MTX'). Vectra DA is multi-biomarker blood test to measure rheumatoid arthritis (RA) disease activity. Vectra DA measures 12 key proteins that represent multiple RA biological pathways. It is validated for use in adults diagnosed with RA. (See Article section for coverage guidelines.) Genetic Testing for Myeloproliferative Disease Myeloproliferative disorders are a group of conditions that cause abnormal growth of blood cells in the bone marrow. They include polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML). The World Health Organization (WHO) further classifies PV, ET, and PMF as Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). MPNs are characterized by an increase in the number of blood cells. (See LCDs for Molecular Pathology for coverage guidelines.) Molecular RBC (red blood cell) Phenotyping Molecular RBC Phenotyping is pretransfusion molecular testing using the HEA BeadChip assay for the following categories of patients: Long term, frequent transfusions anticipated to prevent the development of alloantibodies (e.g. sickle cell anemia, thalassemia or other reason); Autoantibodies or other serologic reactivity that impedes the exclusion of clinically significant alloantibodies (e.g. autoimmune hemolytic anemia, warm autoantibodies, patient recently transfused with a positive DAT, high-titer low avidity antibodies, patients about to receive or on daratumumab therapy, other reactivity of no apparent cause); Suspected antibody against an antigen for which typing sera is not available; and Laboratory discrepancies on serologic typing (e.g. rare Rh D antigen variants) (See LCDs for Molecular Pathology for coverage guidelines) Guidelines Based on the Centers for Medicare & Medicaid Services (CMS) Program Integrity Manual (100-08), this policy addresses the circumstances under which the item or service is reasonable and necessary under the Social Security Act, 1862(a)(1)(A). For laboratory services, a service can be reasonable and necessary if the service is safe and effective; and appropriate, including the duration and frequency that is considered appropriate for the item or service, in terms of whether it is furnished in accordance with accepted standards of medical practice for the diagnosis of the patient's condition; furnished in a setting appropriate to the patient's medical needs and condition; ordered and furnished by qualified personnel; one that meets, but does not exceed, the patient's medical need; and is at least as beneficial as an existing and available medically appropriate alternative. Compliance with the provisions in this policy is subject to monitoring by post payment data analysis and subsequent medical review. Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states "...no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis and treatment of illness or injury...". Furthermore, it has been longstanding CMS policy that "tests that are performed in the absence of signs, symptoms, complaints, or personal history of disease or injury are not covered unless explicitly authorized by statute". Screening services, such as pre-symptomatic genetic tests and services, are those used to detect an undiagnosed disease or disease predisposition, and as such are not a Medicare benefit and not covered by Medicare. Similarly, Medicare may not reimburse the costs of tests/examinations that assess the risk for and/or of a condition unless the risk assessment clearly and directly effects the management of the patient. However, Medicare does cover a broad range of legislatively mandated preventive services to prevent disease, detect disease early when it is most treatable and curable, and manage disease so that complications can be avoided. These services can be found on the CMS website at Any preventive services and tests not listed on the CMS Preventive Services webpage are considered non-covered screening (preventive) tests or services which are not a benefit of the Medicare program. Per 42 Code of Federal Regulations (CFR) section (a) states the following requirements: All diagnostic x-rays tests, diagnostic laboratory tests, and other diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary s specific medical problem. Tests not ordered by the physician who is treating the beneficiary are not reasonable and necessary (see (k)(1)). Also, see Medicare Benefit Policy Manual (100-02), Chapter 15, Section 80.6 for related physician order instructions. Laboratory services must meet all applicable requirements of the Clinical Laboratory Improvement Amendments of 1988 (CLIA), as set forth at 42 CFR part 493. Section 1862(a)(1)(A) of the Act provides that Medicare payment may not be made for services that are not reasonable and necessary. Clinical laboratory services must be ordered and Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 5 of 19

6 used promptly by the physician who is treating the beneficiary as described in 42 CFR (a), or by a qualified nonphysician practitioner, as described in 42 CFR (a)(3). Many applications of the molecular pathology procedures are not covered services given lack of benefit category (preventive service) and/or failure to reach the reasonable and necessary threshold for coverage (based on quality of clinical evidence and strength of recommendation). Furthermore, payment of claims in the past (based on stacking codes) or in the future (based on the new code series) is not a statement of coverage since the service was not audited for compliance with program requirements and documentation supporting the reasonable and necessary testing for the beneficiary. Certain tests and procedures may be subject to prepayment medical review (records requested) and paid claims must be supportable, if selected, for post payment audit by the MAC or other contractors. Tests for diseases or conditions that manifest severe signs or symptoms in newborns and in early childhood or that result in early death (e.g., Canavan disease) could be subject to automatic denials since these tests are not usually relevant to a Medicare beneficiary. Documentation Guidelines Documentation must be adequate to verify that coverage guidelines listed above have been met. Thus, the medical record must contain documentation that the testing is expected to influence treatment of the condition toward which the testing is directed. The laboratory or billing provider must have on file the physician requisition which sets forth the diagnosis or condition that warrants the test(s). Examples of documentation requirements of the ordering physician/nonphysician practitioner (NPP) include, but are not limited to, history and physical or exam findings that support the decision making, problems/diagnoses, relevant data (e.g., lab testing, imaging results). Documentation requirements of the performing laboratory (when requested) include, but are not limited to, lab accreditation, test requisition, test record/procedures, reports (preliminary and final), and quality control record. Documentation requirements for lab developed tests/protocols (when requested) include diagnostic test/assay, lab/manufacturer, names of comparable assays/services (if relevant), description of assay, analytical validity evidence, clinical validity evidence, and clinical utility. Providers are required to code to specificity however, if an unlisted CPT code is used the documentation must clearly identify the unique procedure performed. When multiple procedure codes are submitted on a claim (unique and/or unlisted) the documentation supporting each code should be easily identifiable. If on review the contractor cannot link a billed code to the documentation, these services will be denied based on Title XVIII of the Social Security Act, 1833(e). When the documentation does not meet the criteria for the service rendered or the documentation does not establish the medical necessity for the services, such services will be denied as not reasonable and necessary under Section 1862(a)(1)(A) of the Social Security Act. APPLICABLE CODES The following list(s) of codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this guideline does not imply that the service described by the code is a covered or non-covered health service. Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Guidelines may apply. CPT Code Human Platelet Antigen genotyping (e.g., neonatal alloimmune thrombocytopenia (NAIT) post transfusion purpura (short description); (Effective 01/01/2018) (See the Medicare Advantage Policy Guideline titled Clinical Diagnostic Laboratory Services) IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble) (e.g., glioma), common variants (e.g., R132H, R132C) (Effective 01/01/2018) IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (e.g., glioma), common variants (e.g., R140W, R172M) (Effective 01/01/2018) DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 6 of 19

7 ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (e.g., acquired imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the kinase domain ASXL1 (additional sex combs like 1, transcriptional regulator) (e.g., myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; full gene sequence (Effective 01/01/2018) ASXL1 (additional sex combs like 1, transcriptional regulator) (e.g., myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; targeted sequence analysis (e.g., exon 12) (Effective 01/01/2018) ASPA (aspartoacylase) (e.g., Canavan disease) gene analysis, common variants (e.g., E285A, Y231X) APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g., Maple syrup urine disease) gene analysis, common variants (e.g., R183P, G278S, E422X) BCR/ABL1 (t(9;22)) (e.g., chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative BCR/ABL1 (t(9;22)) (e.g., chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative BCR/ABL1 (t(9;22)) (e.g., chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative BLM (Bloom syndrome, RecQ helicase-like) (e.g., Bloom syndrome) gene analysis, 2281del6ins7 variant BRAF (B-Raf proto-oncogene, serine/threonine kinase) (e.g., colon cancer, melanoma), gene analysis, V600 variant(s) BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants in BRCA1 (i.e., exon 13 del 3.835kb, exon 13 dup 6kb, exon del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb) BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants BRCA1, BRCA2 (breast cancer 1 and 2) (e.g., hereditary breast and ovarian cancer) gene analysis; uncommon duplication/deletion variants BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants (i.e., exon 13 del 3.835kb, exon 13 dup 6kb, exon del 26kb, exon 22 del 510bp, exon 8-9 del 7.1kb) BRCA1 (breast cancer 1) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; full sequence analysis BRCA2 (breast cancer 2) (e.g., hereditary breast and ovarian cancer) gene analysis; known familial variant CEBPA (CCAAT/enhancer binding protein [C/EBP], alpha) (e.g., acute myeloid leukemia), gene analysis, full gene sequence CALR (calreticulin) (e.g., myeloproliferative disorders), gene analysis, common variants in exon 9 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; common variants (e.g., ACMG/ACOG guidelines) CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; known familial variants Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 7 of 19

8 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; duplication/deletion variants CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; intron 8 poly-t analysis (e.g., male infertility) CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17) CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6) Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (e.g., Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis) Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (e.g., drug metabolism), gene analysis, common variant(s) (e.g., *2, *22) (Effective 01/01/2018) CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *7) (Effective 01/01/2018) DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), gene analysis, common variant(s) (e.g., *2A, *4, *5, *6) (Effective 01/01/2018) EGFR (epidermal growth factor receptor) (e.g., non-small cell lung cancer) gene analysis, common variants (e.g., exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q) F9 (coagulation factor IX) (e.g., hemophilia B), full gene sequence (Effective 01/01/2018) F2 (prothrombin, coagulation factor II) (e.g., hereditary hypercoagulability) gene analysis, 20210G>A variant F5 (coagulation Factor V) (e.g., hereditary hypercoagulability) gene analysis, Leiden variant FANCC (Fanconi anemia, complementation group C) (e.g., Fanconi anemia, type C) gene analysis, common variant (e.g., IVS4+4A>T) FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; characterization of alleles (e.g., expanded size and methylation status) FLT3 (FMS-related tyrosine kinase 3) (e.g., acute myeloid leukemia), gene analysis, internal tandem duplication (ITD) variants (i.e., exons 14, 15) G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; common variant(s) (e.g., A, A-) (Effective 01/01/2018) G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; known familial variant(s) (Effective 01/01/2018) G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; full gene sequence (Effective 01/01/2018) G6PC (glucose-6-phosphatase, catalytic subunit) (e.g., Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (e.g., R83C, Q347X) GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, L444P, IVS2+1G>A) Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 8 of 19

9 GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (e.g., nonsyndromic hearing loss) gene analysis; full gene sequence GJB2 (gap junction protein, beta 2, 26kDa; connexin 26) (e.g., nonsyndromic hearing loss) gene analysis; known familial variants GJB6 (gap junction protein, beta 6, 30kDa, connexin 30) (e.g., nonsyndromic hearing loss) gene analysis, common variants (e.g., 309kb [del(gjb6-d13s1830)] and 232kb [del(gjb6-d13s1854)]) HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, G>C, G269S) HFE (hemochromatosis) (e.g., hereditary hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, Constant Spring) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant (Effective 01/01/2018) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence (Effective 01/01/2018) IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) (e.g., familial dysautonomia) gene analysis, common variants (e.g., T>C, R696P) IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemias and lymphomas, B-cell), gene rearrangement analysis to detect abnormal clonal population(s); amplified methodology (e.g., polymerase chain reaction) IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemias and lymphomas, B-cell), gene rearrangement analysis to detect abnormal clonal population(s); direct probe methodology (e.g., Southern blot) IGH@ (Immunoglobulin heavy chain locus) (e.g., leukemia and lymphoma, B-cell), variable region somatic mutation analysis IGK@ (Immunoglobulin kappa light chain locus) (e.g., leukemia and lymphoma, B- cell), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) Comparative analysis using Short Tandem Repeat (STR) markers; patient and comparative specimen (e.g., pre-transplant recipient and donor germline testing, post-transplant non-hematopoietic recipient germline [e.g., buccal swab or other germline tissue sample] and donor testing, twin zygosity testing, or maternal cell contamination of fetal cells) Comparative analysis using Short Tandem Repeat (STR) markers; each additional specimen (e.g., additional cord blood donor, additional fetal samples from different cultures, or additional zygosity in multiple birth pregnancies) (List separately in addition to code for primary procedure) Chimerism (engraftment) analysis, post transplantation specimen (e.g., hematopoietic stem cell), includes comparison to previously performed baseline analyses; without cell selection Chimerism (engraftment) analysis, post transplantation specimen (e.g., hematopoietic stem cell), includes comparison to previously performed baseline analyses; with cell selection (e.g., CD3, CD33), each cell type HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants (Effective 01/01/2018) JAK2 (Janus kinase 2) (e.g., myeloproliferative disorder) gene analysis, p.val617phe (V617F) variant Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 9 of 19

10 KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (e.g., gastrointestinal stromal tumor [GIST], acute myeloid leukemia, melanoma), gene analysis, targeted sequence analysis (e.g., exons 8, 11, 13, 17, 18) KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (e.g., mastocytosis), gene analysis, D816 variant(s) KRAS (Kirsten rat sarcoma viral oncogene homolog) (e.g., carcinoma) gene analysis; variants in exon 2 (e.g., codons 12 and 13) KRAS (Kirsten rat sarcoma viral oncogene homolog) (e.g., carcinoma) gene analysis; additional variant(s) (e.g., codon 61, codon 146) IFNL3 (interferon, lambda 3) (e.g., drug response), gene analysis, rs variant (Effective 01/01/2018) MGMT (O-6-methylguanine-DNA methyltransferase) (e.g., glioblastoma multiforme), methylation analysis MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis MCOLN1 (mucolipin 1) (e.g., Mucolipidosis, type IV) gene analysis, common variants (e.g., IVS3-2A>G, del6.4kb) MTHFR (5,10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C) MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH6 (muts homolog 6 [E. coli]) (e.g. hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH6 (muts homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH6 (muts homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants Microsatellite instability analysis (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (e.g., BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; full sequence analysis MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; known familial variant MECP2 (methyl CpG binding protein 2) (e.g., Rett syndrome) gene analysis; duplication/deletion variants NPM1 (nucleophosmin) (e.g., acute myeloid leukemia) gene analysis, exon 12 variants NRAS (neuroblastoma RAS viral [v-ras] oncogene homolog) (e.g., colorectal carcinoma), gene analysis, variants in exon 2 (e.g., codons 12 and 13) and exon 3 (e.g., codon 61) Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 10 of 19

11 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (e.g., prostate cancer) PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) (e.g., gastrointestinal stromal tumor [GIST]), gene analysis, targeted sequence analysis (e.g., exons 12, 18) PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (e.g., promyelocytic leukemia) translocation analysis; common breakpoints (e.g., intron 3 and intron 6), qualitative or quantitative PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (e.g., promyelocytic leukemia) translocation analysis; single breakpoint (e.g., intron 3, intron 6 or exon 6), qualitative or quantitative PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (e.g., hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant SEPT9 (Septin9) (e.g., colorectal cancer) methylation analysis SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (e.g., adverse drug reaction), gene analysis, common variant(s) (e.g., *5) (Effective 01/01/2018) SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann-Pick disease, Type A) gene analysis, common variants (e.g., R496L, L302P, fsp330) SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (e.g., alpha-1-antitrypsin deficiency), gene analysis, common variants (e.g., *S and *Z) RUNX1 (runt related transcription factor 1) (e.g., acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (e.g., exons 3-8) (Effective 01/01/2018) TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3) (Effective 01/01/2018) TRB@ (T cell antigen receptor, beta) (e.g., leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using amplification methodology (e.g., polymerase chain reaction) TRB@ (T cell antigen receptor, beta) (e.g., leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using direct probe methodology (e.g., Southern blot) Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 11 of 19

12 (T cell antigen receptor, gamma) (e.g., leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) TYMS (thymidylate synthetase) (e.g., 5-fluorouracil/5-FU drug metabolism), gene analysis, common variant(s) (e.g., tandem repeat variant) (Effective 01/01/2018) UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (e.g., irinotecan metabolism), gene analysis, common variants (e.g., *28, *36, *37) VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (e.g., -1639G>A, c c>t) HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (e.g., HbS, HbC, HbE) (Effective 01/01/2018) HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s) (Effective 01/01/2018) HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s) (Effective 01/01/2018) HBB (hemoglobin, subunit beta) (e.g., sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence (Effective 01/01/2018) HLA Class I and II typing, low resolution (e.g., antigen equivalents); HLA-A, -B, -C, - DRB1/3/4/5, and -DQB1 HLA Class I and II typing, low resolution (e.g., antigen equivalents); HLA-A, -B, and - DRB1/3/4/5 (e.g., verification typing) HLA Class I typing, low resolution (e.g., antigen equivalents); complete (i.e., HLA-A, -B, and -C) HLA Class I typing, low resolution (e.g., antigen equivalents); one locus (e.g., HLA-A, -B, or -C), each HLA Class I typing, low resolution (e.g., antigen equivalents); one antigen equivalent (e.g., B*27), each HLA Class II typing, low resolution (e.g., antigen equivalents); HLA-DRB1/3/4/5 and -DQB1 HLA Class II typing, low resolution (e.g., antigen equivalents); one locus (e.g., HLA- DRB1/3/4/5, -DQB1, -DQA1, -DPB1, or -DPA1), each HLA Class II typing, low resolution (e.g., antigen equivalents); one antigen equivalent, each HLA Class I typing, high resolution (i.e., alleles or allele groups); complete (i.e., HLA- A, -B, and -C) HLA Class I typing, high resolution (i.e., alleles or allele groups); complete (i.e., HLA- A, -B, and -C) HLA Class I typing, high resolution (i.e., alleles or allele groups); one locus (e.g., HLA-A, -B, or -C), each HLA Class I typing, high resolution (i.e., alleles or allele groups); one allele or allele group (e.g., B*57:01P), each HLA Class II typing, high resolution (i.e., alleles or allele groups); one locus (e.g., HLA-DRB1, -DRB3, -DRB4, -DRB5, -DQB1, -DQA1, -DPB1, or -DPA1), each HLA Class II typing, high resolution (i.e., alleles or allele groups); one allele or allele group (e.g., HLA-DQB1*06:02P), each Molecular pathology procedure, Level 1 analysis (short description) Molecular pathology procedure, Level 2 analysis (short description) Molecular pathology procedure, Level 3 analysis (short description) Molecular pathology procedure, Level 4 analysis (short description) Molecular pathology procedure, Level 5 analysis (short description) Molecular pathology procedure, Level 6 analysis (short description) Molecular pathology procedure, Level 7 analysis (short description) Molecular pathology procedure, Level 8 analysis (short description) Molecular Pathology/Molecular Diagnostics/Genetic Testing Page 12 of 19