JOHNS HOPKINS HEALTHCARE. Medical Policy: Genetic Testing Department: Health Services Lines of Business: EHP, USFHP, PPMCO, ADVANTAGE MD

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1 Page 1 of 28 ACTION: New Policy: Effective Date: 08/26/2003 Revising : Review Dates: 03/15/04, 10/22/04, 10/21/05, Superseding : 10/19/06, 01/07/08, 01/05/09, 01/07/11, 06/07/13, Archiving : 06/05/15, 09/02/16, 12/02/16, 09/01/17 Retiring : Johns Hopkins HealthCare LLC (JHHC) provides a full spectrum of health care products and services for Employer Health Programs, Priority Partners, Advantage MD, and US Family Health Plan. Each line of business possesses its own unique contract and guidelines which, for benefit and payment purposes, should be consulted to know what benefits are available for reimbursement. Specific contract benefits, guidelines, or policies supersede the information outlined in this policy. SCOPE: This policy presents criteria for medically necessary genetic testing. POLICY: For US Family Health Plan see TRICARE Policy Manual M, February 1, 2008, Diagnostic Genetic Testing and Counseling: Chapter 6, Section 3.1. For Advantage MD, see Medicare Coverage Database: Local Coverage Determination (LCD): Biomarkers Overview (L35062) Local Coverage Determination (LCD): Biomarkers for Oncology (L35396) National Coverage Determination (NCD) for Cytogenetic Studies (190.3) Cross reference with Medical Policies: CMS02.09 BRCA1 and BRCA2 Testing CMS06.03 Fecal DNA Testing CMS04.03 Pharmacogenomics I. General Considerations Please Note A. All genetic tests must be ordered by a licensed physician, nurse practitioner or physician assistant who will ensure that the medical necessity criteria below are met. B. Genetic tests that have received a Hayes Rating of A or B for specific indications and meet the criteria in this policy are considered medically necessary. C. Authorization for genetic tests that have received a Hayes Rating of C MUST be obtained through 2 nd Tier authorization.

2 Page 2 of 28 D. Genetic tests that have received a Hayes Rating of D will be considered experimental and investigational. E. Genetic counseling with documentation of family history and consent is REQUIRED for the following, using the JHHC Genetic Counseling Recommendation Form located at the conclusion of this document: 1. Whole exome sequencing 2. Cardiomyopathy panels 3. Arrthymia QT panels 4. Hereditary ataxia panels 5. Pregnancy pre and post-genetic testing for ANY testing NOT listed in Section I. II. III. Universal Requirements: A. When benefits are provided under the member s contract, JHHC considers genetic testing to establish a molecular diagnosis of an inheritable disease medically necessary when ALL of the following are met: 1. After complete history, physical examination, family history and pedigree analysis, as well as laboratory, imaging or other diagnostic testing as indicated, a specific medical differential diagnosis is established, AND; 2. A specific genetic test is requested, AND; 3. The member displays clinical features, or is at direct risk of inheriting the mutation in question (pre-symptomatic), AND; 4. The result of the test will directly impact the current specific medical treatment being delivered to the member, OR; 5. The result of the test will directly impact current pregnancy or management for the member through the establishment of a molecular diagnosis and recurrence risk, AND; 6. The individual has not had the requested genetic test done previously. Authorization for the genetic tests in Section III of this policy may be obtained through 1 st tier authorization. A. When benefits are provided under the member s contract, JHHC considers Cystic Fibrosis (CF) Carrier Testing medically necessary when EITHER of the following criteria are met: 1. The member is the reproductive partner of a person known to be a CF carrier, OR; 2. The couple is planning a pregnancy or seeking prenatal care, AND EITHER; a. The testing is for a first pregnancy, OR; b. The provider has affirmatively documented that the testing was not performed during previous pregnancies. B. When benefits are provided under the member s contract, JHHC considers Ashkenazi Jewish Panel testing medically necessary when ALL of the following criteria are met: 1. The testing is for the first pregnancy, OR;

3 Page 3 of The provider has affirmatively documented that the testing was not performed during previous pregnancies, AND; 3. The testing is limited to the following conditions: a. Tay Sachs disease b. Canavan disease c. Cystic fibrosis d. Familial dysautonomia e. Bloom syndrome f. Fanconi anemia g. Niemann-Pick disease h. Gaucher disease i. Mucolipidosis Note ~ The testing of the male partner is indicated if the female partner tests positive for any of the above conditions. C. When benefits are provided under the member s contract, JHHC considers Chromosome analysis (karyotype) medically necessary when ANY of the following criteria are met: 1. A woman with a history of previous unexplained stillbirth or repeated (3 or more; 2 or more among infertile couples) first trimester miscarriages, OR; 2. A man whose partner has a history of previous unexplained stillbirth or repeated (3 or more; 2 or more among infertile couples) first trimester miscarriages, OR; 3. A man or woman with a first or second degree relative with a chromosome translocation, OR; 4. One of the following diagnoses is suspected: Turner Syndrome, Down Syndrome, Klinefelter Syndrome, Trisomy X Syndrome, Trisomy 18, Trisomy 13, OR; 5. The parent of a child with a chromosomal abnormality, OR; 6. A fetus with an increased risk for an aneuploidy based on prenatal screening result, OR; 7. A fetus with an increased risk for aneuploidy based on ultrasound findings. D. When benefits are provided under the member s contract, JHHC considers Chromosome Microarray medically necessary when ANY of the following criteria are met: 1. A member with unexplained developmental delay/intellectual disability, OR; 2. A member or fetus with two or more major congenital anomalies not specific to a well-delineated genetic syndrome, OR; 3. A member or fetus with an apparently isolated cardiac anomaly that is highly suggestive of a specific chromosomal condition (e.g. Tetraology of Fallot and 22q11.2 deletion syndrome; suprvalvular aortic stenosis and Williams Syndrome, OR;

4 Page 4 of A member or fetus with a first degree family member with a chromosomal deletion/duplication detectable only on microarray not karyotype (chromosome abnormality). E. When benefits are provided under the member s contract, JHHC considers Fragile X Syndrome, FRAXA (FMR1) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. Individuals with mental retardation, developmental delay, or autism, OR; 2. Individuals planning a pregnancy who have EITHER of the following: a. A family history of fragile X syndrome, OR; b. A family history of undiagnosed mental retardation, OR; 3. Fetuses of known carrier mothers. Prenatal testing of a fetus by amniocentesis or chorionic villus sampling is indicated following a positive Fragile X carrier test in the mother, OR; 4. Women with reproductive or fertility problems associated with elevated levels of follicle stimulating hormone (FSH) (premature ovarian insufficiency), OR; 5. Individuals with late onset tremor or cerebellar ataxia of unknown origin. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers population-based fragile X syndrome screening of individuals who are not in any of the above-listed risk categories experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. F. When benefits are provided under the member s contract, JHHC considers Noninvasive Prenatal Testing using circulating cell-free DNA screening medically necessary in women with a singleton pregnancy determined to be at increased risk of aneuploidy (trisomy 13, 18, and 21) due to ANY of the following conditions: 1. Maternal age 35 years or older at delivery; 2. Fetal ultrasonographic findings indicating an increased risk of aneuploidy; 3. History of a prior pregnancy with a trisomy; 4. Positive screening test result for aneuploidy, including first trimester, sequential, integrated screen, or quadruple screen, OR; 5. Parental balanced robertsonian translocation with increased risk of fetal trisomy 13 or trisomy 21. G. Unless specific benefits are provided under the member s contract, JHHC considers expanded noninvasive prenatal testing using circulating cell-free DNA testing (e.g., Counsyl Informed Pregnancy Screen) experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5.

5 Page 5 of 28 H. Unless specific benefits are provided under the member s contract, JHHC considers noninvasive prenatal testing using circulating cell-free DNA screening not medically necessary for: 1. The primary purpose of sex selection 2. Diagnostic purposes 3. Screening of women with multiple-gestation pregnancy 4. Pregnancies with average or low risk of fetal aneuploidy 5. Detection of micro-deletion syndromes or other chromosomal disorders. I. For PPMCO and USFHP members, noninvasive prenatal testing using circulating cell-free DNA must be conducted by a JHHC participating laboratory provider and may not be performed in regulated space. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers noninvasive prenatal testing using circulating cell-free DNA screening experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria #2-5. IV. Authorization for the genetic tests in Sections IV through VI of this policy MUST be obtained through 2 nd tier authorization. A. When benefits are provided under the member s contract, JHHC considers Adenosis Polyposis Coli (APC) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. Members with greater than 10 colonic polyps, OR; 2. Members with a desmoid tumor, hepatoblastoma, or cribriform-morular variant of papillary thyroid cancer, OR; 3. Members with 1st-degree relatives (i.e., siblings, parents, and offspring) diagnosed with familial adenomatous polyposis (FAP) or with a documented APC mutation. The specific APC mutation should be identified in the affected 1st-degree relative with FAP prior to testing the member, if feasible. Note ~ Full sequence APC genetic testing is considered medically necessary only when it is not possible to determine the family mutation first. B. When benefits are provided under the member s contract, JHHC considers Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, (CADASIL) testing medically necessary when ALL requirements in Universal Requirements section have been met, and EITHER of the following criteria are met: 1. Pre-symptomatic individuals where there is a known mutation in an affected member of the family, OR;

6 Page 6 of Symptomatic individuals, (clinical signs and symptoms of CADASIL include stroke, cognitive defects and/or dementia, migraine, and psychiatric disturbances). C. When benefits are provided under the member s contract, JHHC considers Familial Hypocalciuric Hypercalcemia, (FHH) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. Atypical cases where no family members are available for testing, OR; 2. Families with familial isolated hyperparathyroidism, OR; 3. Infants or children under 10 years of age in whom neonatal hyperparathyroidism, neonatal severe hyperparathyroidism, and FHH are the commonest causes of parathyroid hormone-dependent hypercalcemia, OR; 4. Individuals with overlap in the calcium/creatinine (Ca/Cr) clearance ratio, namely between 0.01 and 0.02, OR; 5. Individuals with the phenotype of FHH whose parents are both normocalcemic (i.e., FHH possibly caused by a de novo CaSR mutation). D. When benefits are provided under the member s contract, JHHC considers Hereditary Hemochromatosis (HFE) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ALL of the following criteria are met: 1. Member who has symptoms consistent with iron overload, AND; 2. Member who has 2 consecutive transferrin saturations of 45 % or more. Note ~ When benefits are provided under the member s contract, JHHC considers genetic testing for HFE gene mutations medically necessary for 1st degree relatives of persons homozygous for HFE gene mutations. Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for hereditary hemochromatosis experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. E. When benefits are provided under the member s contract, JHHC considers Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome (HNPCC) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY ONE of the following criteria are met: 1. Member meets Amsterdam II criteria or revised Bethesda guidelines (see appendix), OR; 2. Member is diagnosed with endometrial cancer before age 50 years, OR; 3. Member has a 1st- or 2nd-degree relative with a disease confirmed to be caused by a HNPCC mutation upon testing of the 1st- or 2nd-degree relative, OR; 4. Member has 5% risk of LS on a validated mutation prediction model (eg, MMRpro, PREMM[1,2,6], MMRpredict). The PREMM[1,2,6] model can be used online at

7 Page 7 of 28 and the HNPCC predict model is available for online use at MMRpro is available for free download at F. When benefits are provided under the member s contract, JHHC considers Hereditary Pancreatitis testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. An unexplained episode of documented pancreatitis and a family history of pancreatitis in a 1st-degree (parent, sibling, child) or 2nd-degree (aunt, uncle, grandparent) relative, OR; 2. An unexplained episode of documented pancreatitis occurring in a child that has required hospitalization, and where there is significant concern that hereditary pancreatitis should be excluded, OR; 3. Recurrent (2 or more separate, documented episodes with hyper-amylasemia) attacks of acute pancreatitis for which there is no explanation (anatomical anomalies, ampullary or main pancreatic strictures, trauma, viral infection, gallstones, alcohol, drugs, hyperlipidemia, etc.), OR; 4. Unexplained (idiopathic) chronic pancreatitis, OR; 5. A 1 st -degree or 2 nd -degree relative with a documented PRSS1 mutation. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for hereditary pancreatitis experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. G. When benefits are provided under the member s contract, JHHC considers Hypertrophic Cardiomyopathy (HCM) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. The individual has a suspected or confirmed diagnosis of HCM and other external causes (hypertension, athlete s heart) have been excluded, OR; 2. Are at-risk for development of HCM, defined as having a close (1st or 2nd degree) relative with established HCM, when there is a known pathogenic gene mutation present in an affected relative. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for HCM experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. H. When benefits are provided under the member s contract, JHHC considers Long QT Syndrome testing medically necessary when ALL requirements in Universal Requirements section have been met, and EITHER of the following criteria are met:

8 Page 8 of Persons with a prolonged QT interval on resting electrocardiogram (a corrected QT interval (QTc) of 450 msec or more in males and 460 msec or more in females) without an identifiable external cause for QTc prolongation (such as heart failure, bradycardia, electrolyte imbalances, certain medications and other medical conditions), OR; 2. Persons with 1st-degree relatives (siblings, parents, offspring) with a defined LQT mutation, or long QT syndrome in sudden death (1st or 2nd degree) close relatives. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for long QT syndrome experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. I. When benefits are provided under the member s contract, JHHC considers Dilated Cardiomyopathy (DCM) testing medically necessary when ALL requirements in Universal Requirements section have been met and EITHER of the following criteria are met: 1. The individual is under age 50 and has a suspected or confirmed diagnosis of DCM and other external causes (alcohol, drug abuse, ischemia) have been excluded, OR; 2. Is at-risk for development of DCM, defined as having a close (1st or 2nd degree) relative with established DCM, when there is a known pathogenic gene mutation present in an affected relative. J. When benefits are provided under the member s contract, JHHC considers Non- Compaction Cardiomyopathy/Left Ventricular Noncompaction (NCCM/LVNC) testing is considered medically necessary when ALL requirements in Universal Requirements section have been met and EITHER of the following criteria are met: 1. The individual has a suspected or confirmed diagnosis of NCCM/LVNC by a ratio of 2.3 or greater on cardiac MRI or echocardiography, OR; 2. Is at-risk for development of NCCM/LVNC, defined as having a close (1st or 2nd degree) relative with established NCCM/LVNC, when there is a known pathogenic gene mutation present in an affected relative. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for NCCM/LVNC experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. K. When benefits are provided under the member s contract, JHHC considers Arrhythmogenic (Right) Ventricular Cardiomyopathy (ARVC/ARVD/ACM) testing medically necessary when ALL requirements in Universal Requirements section have been met, and EITHER of the following criteria are met: 1. The individual has a suspected or confirmed diagnosis of ARVC, OR;

9 Page 9 of Are at-risk for development of ARVC, defined as having a close (1st or 2nd degree) relative with established ARVC, when there is a known pathogenic gene mutation present in an affected relative. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for ARVC/ARVD/ACM experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. L. When benefits are provided under the member s contract, JHHC considers Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) testing medically necessary when ALL requirements in Universal Requirements section have been met, and EITHER of the following criteria are met: 1. The individual has a suspected or confirmed diagnosis of CPVT, OR; 2. Is at-risk for development of CPVT, defined as having a close (1st or 2nd degree) relative with established CPVT, when there is a known pathogenic gene mutation present in an affected relative. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for CPVT experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. M. When benefits are provided under the member s contract, JHHC considers Familial Hypercholesterolemia (FH) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ANY of the following criteria are met: 1. The individual and has a suspected or confirmed diagnosis of FH with an LDL-C of 190mg/dL and total cholesterol level greater than 300 mg/dl, OR; 2. The individual is suspected to have a diagnosis of FH based on xanthomas/xanthelasmas/cornea arcus (younger <45 yo) on physical exam, OR; 3. Is at-risk for development of FH defined as having a close (1st or 2nd degree) relative with established FH, when there is a known pathogenic gene mutation present in an affected relative. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for FH experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. N. MTHFR: JHHC considers genetic testing for polymorphisms (e.g. C677T and A1298C) in the MTHFR gene not medical necessary. O. When benefits are provided under the member s contract, JHHC considers SHOX-related short stature genetic testing medically necessary when ALL requirements in Universal Requirements section have been met and testing is for children and adolescents with short

10 Page 10 of 28 stature and ANY of the following features: 1. Above-average body mass index (BMI), OR; 2. Cubitus valgus (increased carrying angle), OR; 3. Dislocation of the ulna at the elbow, OR; 4. Increased sitting height/height ratio, OR; 5. Madelung deformity of the forearm, OR; 6. Muscular hypertrophy, OR; 7. Reduced arm span/height ratio, OR; 8. Short or bowed forearm. Note ~ Unless specific benefits are provided under the member s contract, JHHC considers genetic testing for SHOX-related short stature experimental and investigational for all other indications, as it does not meet Technology Evaluation Criteria (TEC) #2-5. P. When benefits are provided under the member s contract, JHHC considers Whole Exome Sequencing (WES) testing medically necessary when ALL requirements in Universal Requirements section have been met, and ALL of the following criteria are met: 1. The member has a defined genetic disorder that demonstrates a high degree of genetic heterogeneity or with a phenotype or phenotypes, (e.g. intellectual disability, seizures, multiple congenital anomalies) presumed to have a genetic etiology, AND; 2. Documentation of pretest genetic counseling by a board-certified genetic counselor or geneticist, AND; 3. A single gene or gene panel has been proven to be ineffective, AND; 4. The result of the test will directly impact the current specific medical treatment being delivered to the member, OR; 5. The result of the test will directly impact current pregnancy or management for the member through the establishment of a molecular diagnosis and recurrence risk. V. When benefits are provided under the member s contract, JHHC considers genetic testing for heritable disorders of family members who are not covered under JHHC benefit plans medically necessary when ALL requirements in Universal Requirementssection have been met and ALL of the following conditions are met: A. The information is needed to adequately assess risk in the JHHC member, AND; B. The information will directly impact the current specific medical treatment being delivered to the JHHC member, AND; C. The non-jhhc member's benefit plan, if any, will not cover the test (a copy of the denial letter from the non-jhhc member's benefit plan must be provided or in the case of individuals without a health insurance policy, a written statement documenting a lack of coverage),

11 Page 11 of 28 VI. Genetic Testing for Reproductive Planning and Prenatal Diagnosis A. When benefits are provided under the member s contract, JHHC considers Spinal Muscular Atrophy (SMA) Carrier testing medically necessary when EITHER of the following criteria are met: 1. The member is the reproductive partner of a person known to be a SMA carrier, OR; 2. The couple is planning a pregnancy or seeking prenatal care; AND EITHER a. The testing is for a first pregnancy, OR; b. The provider has affirmatively documented that the testing was not performed during previous pregnancies, OR; 1. The prenatal diagnosis of SMA in the pregnancy of two known carriers. For preimplantation genetic testing of embryos, criteria in Section IV. (C) must be met. B. Universal Carrier Screening Testing 1. Unless specific benefits are provided under the member s contract, JHHC considers all Universal Carrier Screening tests, including but not limited to 23andMe, Counsyl and HerediT Universal, experimental and investigational for all other indications, as they do not meet Technology Evaluation Criteria (TEC) #2-5. C. Genetic Testing of Pre-implantation Embryos (Pre-implantation Genetic Diagnosis (PGD)) 1. When benefits for advanced reproductive technologies (ART), including but not limited to in-vitro fertilization (IVF), are available, JHHC considers pre-implantation genetic diagnosis medically necessary when testing is ordered for a single, recognized genetic disorder with a known inheritance pattern and ANY of the following criteria are met: a. Both partners (or member and donor) are known carriers of a single autosomal recessive disorder, OR; b. One partner (or donor) is a known carrier of a single gene autosomal recessive disorder, AND; the partners (or member and donor) have one offspring that has been diagnosed with that recessive disorder, OR; c. One partner (or donor) is a known carrier of a single gene autosomal dominant disorder, OR; d. One partner (or donor) is a known carrier of a single X-linked disorder, OR; e. One partner (or donor) has a known balanced or unbalanced translocation. D. Genetic Testing of a Fetus Prior to In Utero Surgery 1. When benefits are provided under the member s contract, JHHC considers genetic testing of a fetus prior to proposed in-utero surgery medically necessary when ALL requirements in Universal Requirements section have been met for the following instances: a. The proposed fetal surgery is for ANY of the following indications: i. Ablation of anastomotic vessels in acardiac twins; ii. Insertion of pleuro-amniotic shunt for fetal pleural effusion; iii. Laser ablation of anastomotic vessels in early, severe twin-twin transfusion syndrome;

12 Page 12 of 28 iv. Removal of sacrococcygeal teratoma; v. Repair of myelomeningocele; vi. Resection of malformed pulmonary tissue, or placement of a thoracoamniotic shunt as a treatment of EITHER of the following: Congenital cystic adenomatoid malformation, OR; Extralobar pulmonary sequestration; vii. Twin reversed arterial perfusion (TRAP); viii. Vesico-amniotic shunting as a treatment of urinary tract obstruction; ix. Serial amnioreduction for twin-to-twin transfusion syndrome when the following criteria are met: Women after 26 weeks of gestation, AND; Evidence of abnormal blood flow documented by Doppler studies in one or both fetuses, AND; Evidence of polyhydramnios in the recipient fetus, AND; Donor fetus is oligohydramniotic. x. Fetoscopic tracheal occlusion; xi. Balloon Valvoplasty for critical aortic stenosis; xii. Any fetal anomaly necessitating in utero intervention; APPENDIX: Amsterdam II criteria: At least 3 relatives must have an HNPCC-related cancer*, and ALL of the following criteria must be present: At least 1 of the relatives with cancer associated with HNPC should be diagnosed before age 50 years, AND; At least 2 successive generations must be affected, AND; FAP should be excluded in the colorectal cancer cases (if any), AND; One must be a 1st-degree relative of the other two, AND; Tumors should be verified whenever possible. Revised Bethesda criteria: Member must meet 1 or more of the following criteria Colorectal cancer is diagnosed in a member with 1 or more 1st-degree relatives with an HNPCC-related cancer*, with one of the cancers diagnosed under age 50 years, OR; Colorectal cancer is diagnosed in a member with 2 or more 1st- or 2nd-degree relatives with an HNPCC-related cancer*, regardless of age, OR; Member has colorectal cancer diagnosed before age 50 years, OR;

13 Page 13 of 28 Member has colorectal cancer with microsatellite instability-high (MSI-H) histology, where cancer is diagnosed before age 60 years, OR; Member has synchronous or metachronous HNPCC-related cancers*, regardless of age. * Hereditary nonpolyposis colorectal cancer (HNPCC)-related cancers include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, brain (usually glioblastoma as seen in Turcot Syndrome), and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir-Torre Syndrome. 1st Tier Authorization: Provider may obtain an authorization without submission of documentation when FAXED request states 1st Tier Authorization on request form and FAX cover sheet. 2 nd Tier Authorization: Written authorization required, mailed or FAXED to the appropriate department. THIS POLICY REPLACES: BACKGROUND: CMS07.02 Genetic Counseling Genetic Testing for Colon Cancer Genetic testing is a technique used to examine an individual s DNA. The field of genetic testing has expanded rapidly during the past 20 years, evolving to produce faster sequencing techniques at a lower cost. Sanger sequencing technology was developed in the 1970s and was the technique used to complete the Human Genome Project. Considered the gold-standard of DNA sequencing, Sanger sequencing involves a single-stranded DNA template, a DNA primer, a DNA polymerase, normal deoxynucleosidetriphosphates (dntps), and modified di-deoxynucleosidetriphosphates (ddntps). When these components are combined and subjected to a heating and cooling cycle, specific genes are amplified and their genetic sequence is determined. Single nucleotide polymorphisms (SNPs) are instances of a DNA sample deviating from the reference genome. They can serve as biomarkers for different diseases. Next generation sequencing (NGS) has developed during the past decade and has been largely responsible for the rapidity with which genetic testing has grown. Rather than referring to a single testing method, NGS refers to a group of sequencing technologies (Muzzey, 2015). The theory behind NGS is similar to Sanger sequencing in that it involves fluorescently-labelled base molecules adhering to a DNA template, but because NGS generates more than 250 sequence reads while Sanger sequencing generates one sequence read, the speed with which NGS generates information is much more rapid.

14 Page 14 of 28 Whole exome sequencing (WES) and whole genome sequencing (WGS) has built upon the advances introduced by NGS (Lapin, 2016). These techniques are reflective of the advancement in molecular biology technology sequencing the entire human genome was a twelve-year process in the 1990 s, but it is now completed in a little more than one day (International Human Geome Sequencing Consortium, 2004). A current concern about performing WES and WGS on individuals is the detection of variants of unknown significance (VUS). There genes are variants about which there is no clear guidance regarding their clinical consequence (McDermott, 2015; Schulz, 2015). Their contribution towards disease or drug responses is currently unknown, although future discoveries may result in clarification of the purpose served by particular VUS. Understanding and identifying changes in a patient s genome through genetic testing can aid in clinical decision-making and prove to be cost-effective. The administration of drugs to a patient as a result of genetic testing can also reduce risk/side effects while maximizing benefits in the patient. Interpretation of genetic testing results transcends many disciplines within medicine. Laboratory scientists, pathologists, genetic counselors, physicians, and nurses all collaborate to ensure accurate interpretation of results and to discuss treatment options for patients. CODING INFORMATION: CPT Copyright 2017 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association. Note: The following CPT/HCPCS codes are included below for informational purposes. Inclusion or exclusion of a CPT/HCPCS code(s) below does not signify or imply member coverage or provider reimbursement. The member's specific benefit plan determines coverage and referral requirements. All inpatient admissions require pre-authorization. PRE-AUTHORIZATION REQUIRED Compliance with the provision in this policy may be monitored and addressed through post-payment data analysis and/or medical review audits Employer Health Programs (EHP) **See Specific Summary Plan Description (SPD) Priority Partners (PPMCO) refer to COMAR guidelines and PPMCO SPD then apply policy criteria US Family Health Plan (USFHP), TRICARE Medical Policy supersedes JHHC Medical Policy. If there is no Policy in TRICARE, apply the Medical Policy Criteria Advantage MD, LCD and NCD Medical Policy supersedes JHHC Medical Policy. If there is no LCD or NCD, apply the Medical Policy Criteria

15 Page 15 of 28 CPT DESCRIPTION CODES DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis and duplication analysis, if performed ASPA (aspartoacylase) (eg,canavan disease) gene analysis, common variants APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, Maple syrup urine disease) gene analysis, common variants (eg, R183P, G2785, E422X) BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, 2281del6ins7 variant CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines) CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; intron 8 poly-t analysis (eg, male infertility) CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17) CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN) CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)

16 Page 16 of Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (eg, 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 EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q) F2 (prothrombin, coagulation factor II) (eg, hereditary hypercoagulability) gene analysis, 20210G>A variant F5 (coagulation Factor V) (eg, hereditary hypercoagulability gene analysis, Leiden variant FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia type C) gene analysis, common variant (eg, IVS4+4A>T) FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles FMR1 (Fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and methylation status) FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; internal tandem duplication (ITD) variants (ie, exons 14, 15) FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (eg, D835, I836) G6PC (glucose-6-phosphatase, catalytic subunit) (eg, Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (eg, R83C, Q347X) GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A) GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants GJB6 (gap junction protein, beta 6, 30kDa, connexin 30) (eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(gjb6-d13s1830)] and 232kb [del(gjb6- D13S1854)]) HEXA (hexosaminidase A [alpha polypeptide]) (eg, Tay-Sachs disease) gene analysis, common variants (eg, 1278insTATC, G>C, G269S) HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D) HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring)

17 Page 17 of IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complexassociated protein) (eg, familial dysautonomia) gene analysis, common variants (eg, T>C, R696P) (Immunoglobulin heavy chain locus) (eg, leukemias and lymphomas, B-cell), gene rearrangement analysis to detect abnormal clonal population(s); amplified methodology (eg, polymerase chain reaction) (Immunoglobulin heavy chain locus) (eg, leukemias and lymphomas, B-cell), gene rearrangement analysis to detect abnormal clonal population(s); direct probe methodology (eg, Southern blot) (Immunoglobulin heavy chain locus) (eg, leukemia and lymphoma, B-cell), variable region somatic mutation analysis (Immunoglobulin kappa light chain locus) (eg, 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 (eg, pre-transplant recipient and donor germline testing, post-transplant nonhematopoietic recipient germline [eg, 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 (eg, 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) JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.val617phe (V617F) variant KRAS (v-ki-ras2 Kirsten rat sarcoma viral oncogene) (eg, carcinoma) gene analysis, variants in codons 12 and MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis MCOLN1 (mucolipin 1) (eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb) MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C) MLH1 (mutl homomlog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MLH1 (mutl homomlog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MLH1 (mutl homomlog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis

18 Page 18 of MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH6 (muts homolog 6 [E. coli] (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH6 (muts homolog 6 [E. coli] (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH6 (muts homolog 6 [E. coli] (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants Microsatellite instability analysis (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; full sequence analysis MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; known familial variant MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, exon 12 variants PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer) PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (eg, promyelocytic leukemia) translocation analysis; common breakpoints (eg, intron 3 and intron 6), qualitative or quantitative PML/RARalpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (eg, promyelocytic leukemia) translocation analysis; single breakpoint (eg, intron 3, intron 6 or exon 6), qualitative or quantitative PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyoisus colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; known familial variant PTEN (phosphatase and tensin homolog) (eg, Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; duplication/deletion variant

19 Page 19 of PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsp330) SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (eg, Prader-Willi syndrome and/or Angelman syndrome), methylation analysis SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsis deficiency), gene analysis, common variants (eg, *S and *Z) TRB@ (T cell antigen receptor, beta) (eg, leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using amplification methodology (eg, polymerase chain reaction) TRB@ (T cell antigen receptor, beta) (eg, leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using direct probe methodology (eg, Southern blot) TRG@ (T cell antigen receptor, gamma) (eg, leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37) VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variants (eg, -1639/3673) Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg,snp] by techniques such as restriction enzyme digestion or melt curve analysis) Molecular pathology procedure, Level 2 (eg, 2-10 SNP's, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) Molecular pathology procedure, Level 3 (eg, >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon loss of heterozygosity [LOH], uniparental disomy [UPD]) Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

20 Page 20 of Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, regionally targeted cytogenomic array analysis Molecular pathology procedure, Level 7 (eg, analysis of exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of exons, cytogenomic array analysis for neoplasia) Molecular pathology procedure, Level 8 (eg, analysis of exons by DNA sequence analysis, mutation scannion or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); genomic sequence analysis panel, must include sequencing of at least 9 genes, including FBN1, TGFBR1, TGFBR2, COL3A1, MYH11, ACTA2, SLC2A10, SMAD3, and MYLK Aortic dysfunction or dilation (eg, Marfan syndrome, Loeys Dietz syndrome, Ehler Danlos syndrome type IV, arterial tortuosity syndrome); duplication/deletion analysis panel, must include analyses for TGFBR1, TGFBR2, MYH11, and COL3A Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GA, HEXA, IKBKAP, MCOLN1, and SMPD Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis Exome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator exome (eg, parents, siblings) (List separately in addition to code for primary procedure) Exome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained exome sequence (eg, updated knowledge or unrelated condition/syndrome) Fetal chromosomal aneuploidy (eg, trisomy 21, monosomy X) genomic sequence analysis panel, circulating cell-free fetal DNA in maternal blood, must include analysis of chromosomes 13, 18, and Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis Genome (eg, unexplained constitutional or heritable disorder or syndrome); sequence analysis, each comparator genome (eg, parents, siblings) (List separately in addition to code for primary procedure)