Molecular pathology procedures have broad clinical and research applications.
The following examples of applications may not be relevant to a Medicare
beneficiary or may not meet a Medicare benefit category and/or reasonable and
necessary threshold for coverage. Such examples include Genetic Testing and
Genetic Counseling (when applicable) for:  
  
 Disease Risk,  
 Carrier Screening,  
 Hereditary Cancer Syndromes,  
 Gene Expression Profiling for certain cancers,  
 Prenatal Diagnostic testing,  
 Diagnosis and Monitoring Non-Cancer Indications, and  
 Several Pharmacogenomic applications.  
  
This Local Coverage Determination (LCD) addresses the circumstances under
which the item or service may be reasonable and necessary. For laboratory
services, a service may 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.  
  
Many applications of the molecular pathology procedures are not covered
services given lack of benefit category (e.g., preventive service or screening
for a genetic abnormality in the absence of a suspicion of disease) and/or
failure to the reasonable and necessary threshold for coverage (e.g., based on
quality of clinical evidence and strength of recommendation or when the
results would not reasonably be used in the management of a beneficiary).
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 may not have been audited for compliance with program requirements and
documentation supporting the reasonable and necessary testing for the
beneficiary. Certain molecular pathology 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. Molecular pathology 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.  
  
This LCD gives general guidance to the medically reasonable and necessary
applications of the Molecular Pathology Procedures and Genomic Sequencing
Procedures, described in Current Procedural Terminology (CPT). Coding guidance
is provided in **Molecular Pathology Procedures Article A56199** , attached
below.  
  
 **Indications:**  
Molecular pathology procedures (Tier1 and Tier 2) may be eligible for coverage
when **ALL** of the following criteria are met:

  * Alternative laboratory or clinical tests to definitively diagnose the disorder/identify the condition are unavailable or results are clearly equivocal; AND
  * Availability of a clinically valid test, based on published peer reviewed medical literature; AND
  * Testing assay(s) are Food and Drug Administration (FDA) approved/cleared or if LDT (lab developed test) or LDT protocol or FDA modified test(s) the laboratory documentation should support assay(s) of analytical validity and clinical utility; AND
  * Results of the testing must directly impact treatment or management of the Medicare beneficiary; AND
  * For testing panels, including but not limited to, multiple genes or multiple conditions, and in cases where a tiered approach/method is clinically available, testing would be covered ONLY for the number of genes or test that are reasonable and necessary to obtain necessary information for therapeutic decision making; AND
  * Individual has not previously received genetic testing for the disease/condition. (In general, diagnostic genetic testing for a disease should be performed once in a lifetime.) Exceptions include clinical scenarios whereby repeat testing of somatically-acquired mutations (for example, pre- and post- therapy) may be required to inform appropriate therapeutic decision-making.

**  Limitations:**

  * Any procedures required prior to cell lysis should be reported separately and utilization must be clearly supported based on the application and clinical utility. Such claims may be subject to prepayment medical review.
  * The medically necessary interpretation and report of a molecular pathology test, written by a pathologist, which is above and beyond the report of standard laboratory results may not be reported by Non- physician practitioners (e.g., PhD, scientists etc.); only physicians are eligible to report this service.
  * Testing for quality assurance component of the service is not separately billable.

**_Indications and Limitations of Coverage_**

**ABL1** (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired
imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the
kinase domain is considered medically necessary in patients with acute
lymphoblasic leukemia (ALL) and chronic myeloid leukemia (CML) to guide
therapeutic decision making.

**ATP7B** is considered medically necessary in patients with symptoms of
Wilson's disease to guide therapeutic decision making.

**BCR/ABL** is indicated in patients with suspected CML with either
persistent, unexplained leukocytosis or thrombocytosis. BCR/ABL is considered
medically necessary in the evaluation of individuals with chronic myelogenous
leukemia or BCR-ABL positive acute lymphoblastic leukemia to evaluate treated
individuals who manifest suboptimal response to initial tyrosine kinase
inhibitor therapy or loss of response to tyrosine kinase inhibitor therapy.

__**BLM** (Bloom syndrome, RecQ helicase-like)(e.g. Bloom syndrome) gene
analysis, 2281 del6ins7 variant is considered medically necessary for a
beneficiary who may have Bloom syndrome to confirm diagnosis and guide medical
decision-making.

__**BRAF** gene analysis is considered medically necessary for patients who
have malignant melanoma, non-small cell lung cancer, hairy cell leukemia, or
metastatic colorectal cancer when needed to determine if a Medicare covered
therapy is a reasonable option given the individual's specific clinical
presentation.

__**BRCA1 and BRCA2** genetic testing is considered medically necessary for a
beneficiary with a current diagnosis or a personal history of a cancer
associated with the BRCA mutation who meets one or more of the criteria found
in the most recent version of the NCCN guidelines for Genetic/Familial High-
Risk Assessment: Breast and Ovarian or other evidence based guideline
addressing genetic testing, and the results will be used to benefit the
individual tested in terms of potential to guide therapeutic decision making.

**Cardiology (heart transplant), mRNA** , gene expression profiling by real-
time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing
subtraction of peripheral blood, algorithm reported as rejection risk score is
considered medically necessary for heart transplant patients to guide
therapeutic decision-making. __

**CEBPA** (CCAAT/enhancer binding protein [C/EBP], alpha) (eg, acute myeloid
leukemia), full gene sequence is considered medically necessary in patients
with acute myelogenous leukemia (AML) to guide therapeutic decision making.

__**CALR** (calreticulin) (eg, myeloproliferative disorders), gene analysis,
common variants in exon 9 is considered medically necessary in the initial
diagnostic work-up of BCR-ABL negative, JAK2-negative adults with clinical,
laboratory, or pathological findings suggesting polycythemia vera (PV),
essential thrombocythemia (ET) or primary myelofibrosis (PMF).

**CCND1/IGH** (BCL1/IgH, t)(eg, mantle cell lymphoma) translocation analysis,
major breakpoint, qualitative and quantitative, if performed is considered
medical necessary for patients who have non- Hodgkin's lymphoma to guide
therapeutic decision-making.

__**CFTR** (cystic fibrosis transmembrane conductance regulator) (e.g.cystic
fibrosis) gene analysis, common variants (e.g. ACMG/ACOG guidelines) is
considered medically necessary for a beneficiary who has or may have cystic
fibrosis to guide therapeutic decision-making **.**

**Chimerism analysis** to identify appropriate donors and monitor engraftment
success or disease reoccurrence is considered medically necessary.

**CYP2C6** 19-cytochrome P450 CYP2C6 19-cytochrome P450 Based on the FDA's
Black Box warning for clopidogrel, the effectiveness of clopidogrel is
dependent on its activation to an active metabolite by the cytochrome P450
(CYP) system, principally CYP2C19. CYP2C619 genotyping may be medically
necessary once per lifetime to identify individuals:

  * Who are poor metabolizers of clopidogrel, so that alternative treatment or treatment strategies can be considered
  * Who are poor metabolizers of clopidogrel with acute coronary syndrome or who are undergoing percutaneous coronary intervention

**CYP2C9** (cytochrome P450, family 2, subfamily D polypeptide 9) (e.g., drug
metabolism), gene analysis, is only considered medically necessary for
individuals who have relapsing forms of multiple sclerosis, and require CYP2C9
genotyping for dosing in accordance with the FDA prescribing information for
Mayzent. CYP2C9 testing must include the *1, *2, and *3 alleles that are
necessary to safely dose the FDA-approved drug Mayzent.

**CYP2D6** (cytochrome P450, family 2, subfamily D polypeptide 6) (e.g., drug
metabolism), gene analysis, is only considered medically necessary for
individuals with Huntington's disease for whom doses of tetrabenazine greater
than 50 mg per day are being considered, and for testing prior to the
initiation of CerdelgaTM (eliglustat) for Gaucher's disease.

**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) [when specified as EGFR mutation analysis testing] EGFR
testing is considered medically necessary as a technique to predict treatment
response for individuals with non-small cell lung cancer undergoing treatment
with EGFR tyrosine kinase inhibitor (TKI) therapy (for example, erlotinib
[Tarceva ], gefitinib [Iressa ], or afatinib [Gilotrif ]).

**F2** gene (prothrombin coagulation factor II) and **F5** gene (coagulation
factor V) The F2 and F5 genetic tests are not considered to be clinically
efficacious; therefore, testing is not medically necessary.

**FLT3** is considered medically necessary in patients with acute myeloid
leukemia (AML) to guide therapeutic decision making.

**Gene Testing for Warfarin Response** Pharmacogenomic Testing for Warfarin
Response, gene testing on **CYP2C9 and/or VKORC1** see NCD 90.1 for coverage
information.

**HFE** (hemochromatosis)(hereditary hemochrosis) gene analysis, common
variants (e.g. C282Y, H63D) is considered medically necessary in patients with
iron overload of uncertain etiology (e.g. when the test is used to avoid liver
biopsy in someone when the ferritin and the transferrin saturation are
elevated greater than 45%). The genotyping of patients with iron overload of
uncertain etiology is allowed only once per lifetime.

**HLA** Class I or II typing is considered medically necessary when one of the
following indications is met:

  * Transplantation:

    * Standard of care determination of HLA matching for solid organ transplant (donor/recipient). - Solid organ transplant registries include both serological HLA testing (e.g., crossmatch) and genomic molecular DNA typing. Family members, or unrelated living donors or cadaveric donors who donate bone marrow or a solid organ are HLA tested pre-transplant to determine compatibility with the potential recipients.
    * Standard of care determination of HLA matching for solid organ transplant (donor/recipient). - Solid organ transplant registries include both serological HLA testing (e.g., crossmatch) and genomic molecular DNA typing. Family members, or unrelated living donors or cadaveric donors who donate bone marrow or a solid organ are HLA tested pre-transplant to determine compatibility with the potential recipients.
    * Standard of care identification of determination of HLA matching for hematopoietic stem cell/bone marrow transplantation -allele-level typing will provide clinical guidance for the HLA-A,B,C Class I and DRB1, DQB1,DPB1, and DQA1 Class II loci in the average transplant program because it is well established that mismatches at certain HLA loci between donor-recipients are closely linked to the risk of graft versus host disease. Potential marrow donors may enroll with a national registry such as the United States National Marrow Donor Program or the Canadian Blood Services registry.
  * Disease Association: 
    * Standard of care testing to diagnose certain HLA related diseases/conditions when the testing is supported by the clinical literature and is informative for the direct management of a patient bearing a certain allele(s). It is not expected that more than one test would be required in a given beneficiary's lifetime. Possible covered indications when standard laboratory testing (tissue typing) not adequate: 
      * HLA-B*27 for the diagnosis of certain cases of symptomatic patients with presumed ankylosing spondylitis or related inflammatory disease. HLA-B*27 is covered for ankylosing spondylitis in cases where other methods of diagnosis would not be appropriate or have yielded inconclusive results (NCD 190.1).
      * In the work-up of certain patients with an unclear diagnosis of celiac disease and gluten hypersensitivity usually related to ambiguous standard laboratory results and/or inconsistent biopsy results (e.g., HLA-DQ2 by HLA-DQB1*02 and of DQ8 by HLA-DQB1*0302).
  * Pharmacogenetics: 
    * Standard of care testing to diagnose certain HLA related drug hypersensitivity reactions when the testing is supported by the clinical literature and is informative for the direct management of a patient bearing a certain allele(s) associated to fatal skin drug reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis). It is not expected that more than one test would be required in a given beneficiary's lifetime. Possible covered indications:
      * HLA -B*5701 when testing performed prior to the initiation of an abacavir-containing regime in the treatment of HIV Infection.
      * HLA-B*1502 when genotyping may be useful for risk stratification when the testing is performed prior to the initiation of carbamazepine therapy in the treatment of patients at high risk of having this allele. HLA-B*1502 occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.
      * Identification of HLA compatible platelets for transfusion when standard typing is not adequate.

**HUMAN PLATELET ANTIGEN 1-15** as genotyping for human platelet antigens is
important for identifying woman at risk for neonatal alloimmune
thrombocytopenia (NAIT). Post-transfusion purpura is an immune reaction
against human platelet antigens, often occurring when a woman is sensitized
during pregnancy, then subsequently receives a transfusion. There are few
Medicare beneficiaries for whom this testing will be clinically actionable.

**IGH** @ (Immunoglobulin heavy chain locus) is considered medically necessary
for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL),
and lymphoma, B-cell to guide therapeutic decision making.

**JAK2 V617F** genotyping is considered medically necessary in the initial
diagnostic work-up of BCR-ABL negative, JAK2-negative adults with clinical,
laboratory, or pathological findings suggesting myeloproliferative neoplasm
(MPN) (polycythemia vera (PV), essential thrombocythemia (ET) or primary
myelofibrosis (PMF)) or a myelodysplastic syndrome (MDS). Note: JAK2 (exons 12
and 13) (reported with 81403) is medically necessary in individuals for whom
PV is a strong consideration.

**JAK2** (Janus kinase 2) (eg, myeloproliferative disorder), exon 12 sequence
and exon 13 sequence is considered medically necessary in the initial work-up
of BCR-ABL and JAK2 (V617F variant) negative adults with clinical, laboratory,
or pathological findings suggesting polycythemia vera.

**KIT** (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg,
gastrointestinal stromal tumor [GIST], acute myeloid leukemia, melanoma), gene
analysis, targeted sequence analysis (eg, exons 8, 11, 13, 17, 18) is
considered medically necessary in patients who have GIST, acute myeloid
leukemia (AML) or melanoma to guide therapeutic decision making.

**KIT** (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) (eg,
mastocytosis), gene analysis, D816 variant(s) is considered medically
necessary in patients who have mastocytosis to guide therapeutic decision
making.

**KRAS** gene analysis, variants in codons 12 and 13, is considered medically
necessary in patients with colorectal cancer or non-small cell lung cancer
when needed to determine if a Medicare covered therapy is a reasonable option
given the individual's specific clinical presentation.

**KRAS** (Kirsten rat sarcoma viral oncogene homolog) (e.g., carcinoma) gene
analysis; additional variant(s) (e.g., codon 61, codon 146) is considered
medically necessary in patients with colorectal cancer or non-small cell lung
cancer when needed to determine if a Medicare covered therapy is a reasonable
option given the individual's specific clinical presentation.

**MEN1** (multiple endocrine neoplasia 1) (eg, multiple endocrine neoplasia
type 1, Wermer syndrome), duplication/deletion and CPT code 81405 MEN1
(multiple endocrine neoplasia 1) e.g. multiple endocrine neoplasia type 1,
Wermer syndrome), duplication/deletion analysis) are considered medically
necessary in patients with multiple endocrine neoplasia to guide therapeutic
decision-making.

**MET** proto-oncogene, receptor tyrosine kinase, is considered medically
necessary in patients with non-small cell lung cancer when needed to determine
if a Medicare covered therapy is a reasonable option given the individuals
specific clinical presentation.

**MGMT** (O-6-methylguanine-DNA methyltransferase) (e.g., glioblastoma
multiforme), methylation analysis) is considered medically necessary in
patients with malignant brain neoplasm to guide therapeutic decision making.

**MPL** (myeloproliferative leukemia virus oncogene, thrombopoietin receptor,
TPOR) (eg, myeloproliferative disorder), common variants (eg, W515A, W515K,
W515L, W515R) is considered medically necessary in the initial work-up of BCR-
ABL negative, JAK2 negative, and CALR negative adults with clinical,
laboratory, or pathological findings suggesting thrombocytosis, essential
thrombocythemia (ET), or primary myelofibrosis (PMF).

**MPL** (myeloproliferative leukemia virus oncogene, thrombopoietin receptor,
TPOR) (eg, myeloproliferative disorder), exon 10 sequence is considered
medically necessary in the initial work-up of BCR-ABL negative, JAK2 negative,
and CALR negative adults with clinical, laboratory, or pathological findings
suggesting thrombocytosis, essential thrombocythemia (ET), or primary
myelofibrosis (PMF).

**MTHFR** (5,10-methyenetetrahydrofolate reductase) (e.g. hereditary
hypercoaguability), gene analysis, common variants(e.g., EG, 677T, 1298C) is
not considered to be clinically efficacious; therefore, testing is not
medically necessary.

**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 and
is considered medically necessary in individuals who have colorectal cancer
(CRC) diagnosed at less than or equal to 70 years of age, and those greater
than 70 years who meet the revised Bethesda Lynch Syndrome (LS) guidelines to
guide therapeutic decision-making. Despite the high penetrance of CRC and
endometrial cancer and recommendations of consideration for screening
unaffected first-degree relatives following diagnosis of an LS proband,
testing of genetic carriers who are unaffected with a Lynch- related cancer is
not a Medicare benefit, and is statutorily excluded from coverage.

MSI testing is also required by FDA for the clinical use of Keytruda
(pembrolizumab) in a restricted population of patients. These are patients who
have unresectable or metastatic solid tumors who have progressed following
prior treatment and have no satisfactory alternative options. When Keytruda
(pembrolizumab) is a potential clinically appropriate therapeutic choice, MSI
testing is medically necessary in these patients. Because this is a wide-
ranging population of advanced cancer patients, ICD-10 specificity is
impractical, therefore use an ICD-10 appropriate for the tumor type and
location.

**MYD88** genetic test is considered medically necessary in patients with
Marginal Zone Lymphoma (MZL), Waldenstrom's Macroglobulinemia (WM) and
Lymphoplasmacytic Lymphoma (LPL) to guide therapeutic decision-making.

**NPM1 (** nucleophosmin) is considered medically necessary in patients with
acute myeloid leukemia (AML) to guide therapeutic decision making.

**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) is considered medically necessary in patients with
colorectal cancer when needed to determine if a Medicare covered therapy is a
reasonable option given the individual's specific clinical presentation.

**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 is considered medically necessary to guide
therapeutic decision-making in patients with the following findings:

  * estrogen-receptor positive, node-negative carcinoma of the breast
  * estrogen-receptor positive micrometastases of carcinoma of the breast, and
  * estrogen-receptor positive breast carcinoma with 1-3 positive nodes.

**PDGFRA** (platelet-derived growth factor receptor, alpha polypeptide) (e.g.,
gastrointestinal stromal tumor [GIST]), gene analysis, targeted sequence
analysis (eg, exons 12, 18) is considered medically necessary in patients with
PDGFRA-associated chronic eosinophilic leukemia or GIST caused by mutations in
the PDGFRA gene to guide therapeutic decision making.

**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 is considered
medically necessary in patients with promyelocytic leukemia.

**Prosigna  Breast Cancer Prognostic Gene Signature Assay** is considered
medically necessary in patients who have undergone surgery in conjunction with
locoregional treatment consistent with standard of care, either as:

  * A prognostic indicator for distant recurrence-free survival at 10 years in post- menopausal women with Hormone Receptor-Positive (HR+), lymph node-negative, Stage I or II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors.
  * A prognostic indicator for distant recurrence-free survival at 10 years in post- menopausal women with Hormone Receptor-Positive (HR+), lymph node-positive (1-3 positive nodes}, Stage II breast cancer to be treated with adjuvant endocrine therapy alone, when used in conjunction with other clinicopathological factors. The device is not intended for patients with 4 or more positive nodes

**RARS** (SF3B1 mutation) is considered medically necessary in patients with
Myelodysplastic Syndrome to guide therapeutic decision-making.

**RET** (ret-proto-oncogene) is considered medically necessary in patients
with medullary CA of thyroid, multiple endocrine neoplasia, pheochromocytoma,
and parathyroid tumors) to guide therapeutic decision making.

**ROS** proto-oncogene 1, receptor tyrosine kinase, is considered medically
necessary in patients with non-small cell lung cancer when needed to determine
if a Medicare covered therapy is a reasonable option given the individuals
specific clinical presentation.

**SERPINA1** (serpin peptidase inhibitor, clade A, alpha-1- antiproteinase,
antitrypsin, member 1) (e.g., antitrypsin deficiency), gene analysis, common
variants (e.g. *S and *Z) is considered medically necessary for patients who
have antitrypsin deficiency to guide therapeutic decision-making.

**Targeted genomic sequence analysis panel, solid organ neoplasm** , DNA
analysis, and RNA analysis when performed, 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 is considered not medically necessary except when
used to guide treatment decision making in individuals with non-small cell
lung cancer (please refer to LCD L36376).

**TP53** (tumor protein 53) (e.g. tumor samples), targeted sequence analysis
of 2-5 exons, and CPT code 81405 TP53 (tumor protein 53) (e.g. Li-Fraumeni
syndrome, tumor samples), full gene sequence or targeted sequence analysis of
>5 exons are considered medically necessary in individuals who have Acute
Myelogenous Leukemia, chronic lymphocytic leukemia (CLL), or Myelodysplastic
Disease to guide therapeutic decision-making.

**TRB** @ (T CELL antigen receptor, BETA) (e.g., leukemia and lymphoma), gene
rearrangement analysis to detect abnormal cloning population(s); using
amplification methodology is considered necessary to guide therapeutic
decision-making for individuals with acute lymphoid leukemia, aplastic anemia,
and T cell prolymphocytic leukemia.

**TRG** @ (T CELL antigen receptor, GAMMA ) (e.g., leukemia and lymphoma),
gene rearrangement analysis , evaluation to detect abnormal cloning
population(s) are considered medically necessary to guide therapeutic
decision-making for individuals with acute lymphoid leukemia, aplastic anemia,
and T cell prolymphocytic leukemia and mastocytosis.  
  

**Tier 2 Covered Gene/Gene Combinations**

Limited coverage may be provided for specific genes reported below:

ACE  
---  
ATP7B (ATPase, Cu++ transporting, beta polypeptide)  
CCND1/IGH  
CBFB-MYH11  
CDKN2A (cyclin-dependent kinase inhibitor 2A)  
E2A/PBX1  
EML4-ALK  
ETV6-RUNX1  
EWSR1/ERG  
EWSR1/FLI1  
EWSR1/WT1  
F11coagulation factor XI  
F13B  
F5  
F7  
F8 (coagulation factor VIII)  
FGB  
FIP1L1-PDGFR  
FOXO1/PAX3  
FOXO1/PAX7  
MEN1 (multiple endocrine neoplasia 1) (eg, multiple endocrine neoplasia type
1, Wermer syndrome), duplication/deletion  
MEN1 (multiple endocrine neoplasia 1) (eg, multiple endocrine neoplasia type
1, Wermer syndrome), full gene sequence  
MUTYH (mutY homolog [E.coli])  
NPM/ALK  
PAX8/PPARG  
PRSS1 (protease, serine, 1 [trypsin 1])  
RARS (SF3B1  
RUNX1/RUNX1T1  
TP53 (tumor protein 53) (e.g. tumor samples), targeted sequence analysis of
2-5 exons  
TP53 (tumor protein 53) (e.g. Li-Fraumeni syndrome, tumor samples), full gene
sequence or targeted sequence analysis of >5 exons  
VHL (von Hippel-Lindau tumor suppressor)  
  
**Tier 2 Individual Review Codes/Gene Combinations**

Any genetic test reported with a Tier 2 CPT code, not listed above or below,
is subject to individual review.

**Tier 2 Non-covered Codes/Gene Combinations**

The following individual Tier 2 genetic tests are unlikely to impact
therapeutic decision-making, directly impact treatment, outcome and/or
clinical management in the care of the beneficiary and will be denied as not
medically necessary (Please note that this list of non-covered genes is not
exhaustive, and the fact that a specific gene is not mentioned does not mean
it is covered. In addition, many genes have several names that are used. The
most common names have been used in this policy):

ABCC8  
---  
ACADM  
ACADS (acyl-CoA dehydrogenase)  
ACADVL (acyl-CoA dehydrogenase, very long chain)  
ADRB2  
AGTR1  
AIRE (APSI)  
AKT1  
ANG (angiogenin, ribonuclease, RNase A family, 5)  
APOE  
AQP2 (aquaporin 2 [collecting duct])  
AR (androgen receptor)  
ARX (aristaless related homeobox)  
ATN1  
BTD (biotinidase)  
C9orf72  
CASR (CAR, EIG8, extracellular calcium-sensing receptor, FHH, FIH, GPRC2A,
HHC, HHC1, NSHPT, PCAR1)  
CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular
dystrophy type 1C), full gene sequence  
CBS (cystathionine-beta-synthase)  
CCR5  
CDKL5 (cyclin-dependent kinase-like 5)  
CFH/ARMS2  
Chromosome 18q-  
CLRN1  
CLRN1 (clarin 1)  
CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1)  
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide2)  
CYP21A2  
DEK/NUP214  
DLAT (dihydrolipoamide S-acetyltransferase)  
DLD (dihydrolipoamide dehydrogenase)  
DMPK (dystrophia myotonica-protein kinase (DM gene and DM1)  
DMPK (dystrophia myotonica-protein kinase)  
DYT1 (TOR1A)  
EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth)  
F8 (coagulation factor VIII)  
F8 (coagulation factor VIII)  
FGFR2 (fibroblast growth factor receptor 2) (2 EXONS)  
FGFR3  
FGFR3  
FGFR3 (fibroblast growth factor receptor 3) (4 EXONS)  
FGFR3 (fibroblast growth factor receptor 3) one exon  
FKRP (Fukutin related protein)  
FOXG1 (forkhead box G1)  
FSHMD1A (facioscapulohumeral muscular dystrophy 1A)  
FSHMD1A (facioscapulohumeral muscular dystrophy 1A)  
FXN (frataxin)  
GALT (galactose-1-phosphate uridylyltransferase)  
GALT (galactose-1-phosphate uridylyltransferase)  
GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full
gene sequence  
H19  
HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA
hydratase [trifunctional protein] alpha subunit)  
HAX1 (HAX1_HUMAN, HCLS1- associated protein X-1, HCLSBP1, HS1-associating
protein X-1, HS1 binding protein, HS1-binding protein 1, HS1BP1, HSP1BP-1)  
HEXA (hexosaminidase A, alpha polypeptide)  
HNF1B (HNF1 homeobox B)  
HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog Costello syndrome)  
HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog)  
HTT (huntingtin)  
IL28B  
IVD  
KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10)  
KCNQ10T1 (KCNQ1 overlapping transcript 1)  
KIF6  
Level 8 Molecular Pathology Procedures  
Level 9 Molecular Pathology Procedures  
LMNA (lamin A/C)  
LPA intron 25 genotype  
MEFV (Mediterranean fever) (eg, familial Mediterranean fever)  
MEG3/DLK1  
MEK1  
MLH1  
MLL/AFF  
MPZ (myelin protein zero)  
MT-ATP6  
MT-ND4, MT-ND6  
MT-ND5 mitochondrially encoded tRNA leucine 1 [UUA/G] mitochondrially encoded
NADH dehydrogenase 5)  
MT-RNR1 (mitochondrially encoded 12S RNA)  
MT-RNR1 (mitochondrially encoded 12S RNA)  
MT-TK (mitochondrially encoded tRNA lysine)  
MT-TL1  
MT-TS1  
MT-TS1 (mitochondrially encoded tRNA serine 1)  
MUTYH (mutY homolog [E. coli])  
NF2 (neurofibromin 2 [merlin])  
NSD1 (nuclear receptor binding SET domain protein 1)  
PAH (phenylalanine hydroxylase)  
PAX2 (paired box 2)  
PDHA1 (pyruvate dehydrogenase [lipoamide] alpha1)  
PIK3C, PI3Ks, PI(3)Ks, PI-3Ks  
POLG (polymerase [DNA directed], gamma)  
PRKAG2 (protein kinase, AMP-activated, gamma 2 non-catalytic subunit)  
PRSS1 (protease, serine, 1 [trypsin 1])  
PTPN11 (protein tyrosine phosphatase, non-receptor type 11)  
RET (ret-proto-oncogene) (eg, Hirschsprung disease), full gene sequence  
SCA1  
SDA2  
SLC25A4 (solute carrier family 25 [mitochondrial carrier; adenine nucleotide
translocation]  
SLC9A6 (solute carrier family 9 [sodium/hydrogen exchanger] member 6)  
SMN1  
SMN1 (survival of motor neuron 1, telomeric)  
SMN1/SMN2 (survival of motor neuron 1, telomeric/survival of motor neuron 2,
centromeric)  
SOS1 (son of sevenless homolog 1)  
SPG4  
TAZ (tafazzin)  
TOR1A  
TRD  
TSC1 (tuberous sclerosis 1)  
TSC2 (tuberous sclerosis 2)  
UBE3A (ubiquitin protein ligase)  
UPD (Uniparental disomy)  
VEGFR2 (CD309, FLK1, VEGFR)  
VWF (von Willebrand factor)  
  


**HUMAN PLATELET ANTIGEN 1-15**

Coverage of (HUMAN PLATELET ANTIGEN 1-15) as genotyping for human platelet
antigens is important for identifying woman at risk for neonatal alloimmune
thrombocytopenia (NAIT). Post-transfusion purpura is an immune reaction
against human platelet antigens, often occurring when a woman is sensitized
during pregnancy, then subsequently receives a transfusion. There are few
Medicare beneficiaries for whom this testing will be clinically actionable.

**_IFNL3_ (IL28B)**

Newer treatment regimens are replacing PEG-interferon therapies. Per UpToDate:
"Several clinical features that were predictors of response to interferon-
based regimens are no longer relevant to combination direct-acting antiviral
(DAA) regimens...Polymorphisms in the IL28B gene, which encodes interferon
lambda 3, effectively predicted responses to treatment with interferon-based
therapies and accounted for a significant proportion of the differential
response observed in patients of certain races, such as patients of African
descent. In contrast, neither non-CC IL28 genotype nor race has consistently
been associated with lower sustained virologic response (SVR) rates in
multiple trials and cohort studies of contemporary DAA combination regimens.
Although some studies have suggested a limited impact of IL28 genotype or race
on SVR rates with DAA regimens, the magnitude of the impact is small when
appropriate regimens are used and not sufficient enough to recommend IL28B
genotype testing in routine clinical practice."

_**G6PD**_

The WHO recommends testing of drugs to predict for risk of hemolysis in G6PD
deficient individuals if the drugs are to be prescribed in areas of high
prevalence of G6PD deficiency.

**  Reconsideration Request- October 2022**

**IGH and TP53**

NCCN Category 2A designation supports coverage of IGH and TP53 gene testing
for Chronic Lymphocytic Leukemia (CLL) patients.



**HUMAN PLATELET ANTIGEN 1-15**

There are too few Medicare beneficiaries that would both be pregnant and at
risk for neonatal alloimmune thrombocytopenia to warrant coverage outside of
appeal.

**_IFNL3_ (IL28B)**

Given that PEG interferon treatment of HCV is becoming obsolete, so is related
companion genetic testing. In addition, when used and IL28 testing is
negative, there is little evidence that clinicians still do not use the PEG-
interferon-alpha-containing regimens despite the unfavorable response
genotype. The testing is, therefore, considered not medically necessary.

**_G6PD_**

While initial and even confirmatory testing for G6PD deficiency when certain
high-risk drugs are used is appropriate, the use of molecular/genetic/DNA
methods is not established. General screening, not to be confused with testing
immediately before prescription of high-risk drugs, is not a Medicare benefit.

**IGH and TP53**

Coverage is provided for IGH and TP53 genes to facilitate decision-making in
the medical management of Chronic Lymphocytic Leukemia (CLL) patients. NCCN
Category 2A designation supports coverage of IGH and TP53 gene testing for
Chronic Lymphocytic Leukemia (CLL) patients.