JOHNS HOPKINS HEALTHCARE

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1 Page 1 of 15 ACTION: New Policy: Effective Date: 08/26/2003 Revising : Review Dates: 03/15/2004, 10/22/2004, Superseding : 10/21/2005, 10/19/2006, 01/07/2008, Archiving : 01/05/2009, 01/07/2011, 06/07/2013, 06/05/2015 Retiring : Johns Hopkins HealthCare (JHHC) provides a full spectrum of health care products and services for Employer Health Programs, Priority Partners, 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. POLICY: For US Family Health Plan see TRICARE Policy Manual M, February 1, 2008, Diagnostic Genetic Testing and Counseling: Chapter 6, Section 3.1. I. All genetic testing, with the exception of routine karyotype and Fragile X, requires prior authorization whether performed in an inpatient or outpatient setting. II. 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. III. Johns Hopkins HealthCare (JHHC) considers genetic testing to establish a molecular diagnosis of an inheritable disease medically necessary when ALL of the following are met: A. 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 B. A specific genetic test is requested; AND C. The member displays clinical features, or is at direct risk of inheriting the mutation in question (pre-symptomatic); AND D. The result of the test will directly impact the current specific medical treatment being delivered to the member; AND E. The individual has not had the genetic testing done previously; AND F. The test requested has a Hayes Rating of A or B. IV. All genetic tests with a Hayes Rating of D will be considered investigational. V. Genetic Testing of Family Members A. Genetic testing of JHHC members is excluded from coverage under JHHC s benefit plans

2 Page 2 of 15 if the testing is performed primarily for the medical management of other family members who are not covered under a JHHC benefit plan. B. JHHC considers genetic testing for heritable disorders of family members who are not covered under JHHC benefit plans medically necessary when ALL of the following conditions are met: 1. The information is needed to adequately assess risk in the JHHC member; AND 2. The information will directly impact the current specific medical treatment being delivered to the JHHC member; AND 3. 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). VI. Genetic Testing for Reproductive Planning and Prenatal Diagnosis A. For Non-Invasive Prenatal Testing for Fetal Aneuploidy (NIPT) see policy CMS B. Cystic Fibrosis (CF) Carrier Testing is considered 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. C. Spinal Muscular Atrophy (SMA) Carrier Testing is considered medically necessary when ALL of the following criteria are met: 1. The diagnosis of persons with hypotonia and muscle weakness who are suspected of having spinal muscular atrophy; OR 2. The identification of SMN1 deletion carriers in the families of persons with SMA (subject to limitations in Section V above); OR 3. The prenatal diagnosis of SMA in the pregnancy of two known carriers. For preimplantation genetic testing of embryos, criteria in Section VI.(F) must be met. D. Ashkenazi Jewish Panel Testing is considered medically necessary when ALL of the following criteria are met: 1. The testing is for the first pregnancy; OR 2. 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

3 Page 3 of 15 i. Mucolipidosis 4. The testing of the male partner is indicated if the female partner tests positive for any of the above conditions. E. Universal Carrier Screening Testing 1. Unless specific benefits apply, JHHC considers all Universal Carrier Screening tests, including but not limited to Counsyl and HereditT Universal, investigational, as they do not meet Technology Evaluation Criteria #2-5. F. 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 ONE of the following criterion is 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 c. The partners (or member and donor) have one offspring that has been diagnosed with that recessive disorder; OR d. One partner (or donor) is a known carrier of a single gene autosomal dominant disorder, OR e. One partner (or donor) is a known carrier of a single X-linked disorder; OR f. One partner (or donor) has a known balanced or unbalanced translocation. G. Genetic Testing of a Fetus Prior to In Utero Surgery 1. JHHC considers genetic testing of a fetus prior to proposed in-utero surgery medically necessary when ALL of the following criteria are met: 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; 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

4 Page 4 of 15 THIS POLICY REPLACES: BACKGROUND: 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. AND x. ALL criteria in Section III above are met. CMS07.02 Genetic Counseling Genetic Testing for Colon Cancer With the advancement of technology, the medical field has seen a parallel in the advancement and utilization of genetic testing. Genetic testing is a type of medical test that allows medical professionals to detect changes in an individual s DNA. These changes can be detected in chromosomes, genes, and/or proteins. Genetic testing and next generation sequencing have a profound range of benefits. Such benefits may include: Diagnose disease and assess severity Associate changes in DNA with an already diagnosed disease Aid in clinical decision-making/personalized medicine Detect disease prevalence/risk Screen for abnormalities in children Single nucleotide polymorphisms (SNP s) can serve as biomarkers for many different diseases. Understanding and identifying changes in a patient s genome through genetic testing or nextgeneration sequencing 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 2015 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

5 Page 5 of 15 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. This list of CPT/HCPCS codes is not all inclusive: 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 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

6 Page 6 of 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) 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

7 Page 7 of 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) 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) IGH@ (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) IGH@ (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) IGH@ (Immunoglobulin heavy chain locus) (eg, leukemia and lymphoma, B-cell), variable region somatic mutation analysis IGK@ (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, posttransplant non-hematopoietic 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 13

8 Page 8 of Long QT syndrome gene analysis (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, ANTA1 and AKN2); full sequence analysis Long QT syndrome gene analysis (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, ANTA1 and AKN2); known familial sequence variant Long QT syndrome gene analysis (eg, KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, ANTA1 and AKN2); duplication/deletion variants MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary nonpolyposis 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 nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary nonpolyposis 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

9 Page 9 of 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 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)

10 Page 10 of (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) (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) (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) 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)

11 Page 11 of 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 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) Genome (eg, unexplained constitutional or heritable disorder or syndrome); re-evaluation of previously obtained genome sequence (eg, updated knowledge or unrelated condition/syndrome) Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); genomic sequence analysis panel, must include sequencing of at least 60 genes, including CDH23, CLRN1, GJB2, GPR98, MTRNR1, MYO7A, MYO15A, PCDH15, OTOF, SLC26A4, TMC1, TMPRSS3, USH1C, USH1G, USH2A, and WFS Hearing loss (eg, nonsyndromic hearing loss, Usher syndrome, Pendred syndrome); duplication/deletion analysis panel, must include copy number analyses for STRC and DFNB1 deletions in GJB2 and GJB6 genes Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS Hereditary colon cancer syndromes (eg, Lynch syndrome, familial adenomatosis polyposis); duplication/deletion gene analysis panel, must include analysis of at least 8 genes, including APC, MLH1, MSH2, MSH6, PMS2, EPCAM, CHEK2, and MUTYH

12 Page 12 of Nuclear encoded mitochondrial genes (eg, neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, 5-50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed Targeted genomic sequence analysis panel, hematolymphoid neoplasm or disorder, DNA and RNA analysis when performed, 5-50 genes (eg, BRAF, CEBPA, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KRAS, KIT, MLL, NRAS, NPM1, NOTCH1), interrogation for sequence variants, and copy number variants or rearrangements, or isoform expression or mrna expression levels, if performed Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A Unlisted molecular pathology procedure Oncology (breast), mrna, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score Androsterone Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like-1)

13 Page 13 of Chromosome analysis for breakage syndromes; baseline Sister Chromatid Exchange (SCE) cells Chromosome analysis for breakage syndromes; baseline breakage, score cells, count 20 cells, 2 karyotypes (eg, for ataxia telangiectasia, Fanconi anemia, fragile X) Chromosome analysis for breakage syndromes; score 100 cells, clastogen stress (eg, diepoxybutane, mitomycin C, ionizing radiation, UV radiation) Chromosome analysis; count 5 cells, 1 karyotype, with banding Chromosome analysis; count cells, 2 karyotypes, with banding Chromosome analysis; count 45 cells for mosaicism, 2 karyotypes, with banding Chromosome analysis; analyze cells Chromosome analysis, amniotic fluid or chorionic villus, count 15 cells, 1 karyotype, with banding Chromosome analysis, in situ for amniotic fluid cells, count cells from 6-12 colonies, 1 karyotype, with banding Molecular cytogenetics; DNA probe, each (eg, FISH) Molecular cytogenetics; chromosomal in situ hybridization, analyze 3-5 cells (eg, for derivatives and markers) Molecular cytogenetics; chromosomal in situ hybridization, analyze cells (eg, for microdeletions) Molecular cytogenetics; interphase in situ hybridization, analyze cells Molecular cytogenetics; interphase in situ hybridization, analyze cells Consultation and report on referred material requiring preparation of slides HCPCS CODE DESCRIPTION S3840 DNA analysis for germline mutations of the RET proto-oncogene for susceptibility to multiple endocrine neoplasia type 2 S3841 Genetic testing for retinoblastoma S3842 Genetic testing for Von Hippel-Lindau disease S3844 DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness S3845 Genetic testing for alpha-thalassemia S3846 Genetic testing for hemoglobin E beta-thalassemia S3849 Genetic testing for Niemann-Pick disease S3850 Genetic testing for sickle cell anemia S3852 DNA analysis for APOE epsilon 4 allele for susceptibility to Alzheimer s disease S3853 Genetic testing for myotonic muscular dystrophy S3854 Gene expression profiling panel for use in the management of breast cancer treatment S3861 Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for suspected Brugada syndrome S3865 Comprehensive gene sequence analysis for hypertrophic cardiomyopathy

14 Page 14 of 15 S3866 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family REFERENCES STATEMENT: Analyses of the scientific and clinical references cited below were conducted and utilized by the Johns Hopkins HealthCare (JHHC) Medical Policy Team during the development and implementation of this medical policy. Per NCQA standards, the Medical Policy Team will continue to monitor and review any newly published clinical evidence and adjust the references below accordingly if deemed necessary. CLINICAL: 1. Grada, A., Weinbrecht, K. (2013). Next-generation sequencing: Methodology and application. Journal of Investigative Dermatology, 133, e Robson, M., Storm, C., Weitzel, J., et al. (2010). American Society of Clinical Oncology Policy Statement Update: Genetic and genomic testing for cancer susceptibility. J Clin Oncol., 28, Foster, M., Mulvihill, J., et al. (2009). Evaluating the utility of personal genomic information. Genet Medicine, 11, Domchek, S., Friebel, T., Singer, C., et al. (2010). Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA, 304, Wall, D.P., Tonellato, P.J. (2012). The future of genomics in pathology. F1000 Med Rep., 4, Hayes, Inc. Genetic Test Evaluation (GTE): HEALTH PLAN: 7. Aetna Clinical Policy Bulletin, (2015, May 6). Genetic Testing Policy; Number: Retrieved from: 8. Aetna Clinical Policy Bulletin, (2014, July 15). Fetal Surgery in Utero; Number: 0449 found at: REGULATORY: 9. TRICARE POLICY MANUAL M, February 1, Chapter 6, Section 3.1. Diagnostic Genetic Testing, Authority 32 CFR 199.4(a)(1)(i). Retrieved from:

15 Page 15 of Centers for Medicare and Medicaid (CMS), PUBLIC LAW MAY 21, Retrieved from: COMAR: 2010 Individual Medicare Supplement Policies-Plans A through D, F, G, K through N, (Revised 2010, April 28). Prohibition against Use of Genetic Information and Requests for Genetic Testing: C. Retrieved from: Shuren, J., (2010, July 22). 12. U.S. Food and Drug Administration (FDA). Direct-to-Consumer Genetic Testing and the Consequences to the Public. Retrieved from: Testimony/ucm htm. 13. U.S. Food and Drug Administration (FDA), (2011, July 8). Product Classification: Test Factor V Leiden DNA Mutations Detection Systems. Medical Device 510(k) Retrieved from: National Human Genome Research Institute. National Institute of Health. (2015). Access: