CAM 166

General Genetic Testing, Germline Disorders

Category:Laboratory   Last Reviewed:April 2021
Department(s):Medical Affairs   Next Review:April 2022
Original Date:April 2017    

Description 
Germline variants or mutations are defined as genetic alterations that occur within the germ cells (egg or sperm), such that the alteration becomes incorporated into the DNA of every cell in the body of the offspring. It may also be called hereditary mutation (Li et al., 2017; NCI, 2017). 

Genetic testing refers to the use of technologies that identify genetic variation, which include genomic, transcriptional, proteomic, and epigenetic alterations, for the prevention, diagnosis, and treatment of disease (Li et al., 2017; Raby, 2021).

Regulatory Status
Numerous FDA-approved tests exist for the assessment of mutations. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Policy  

  1. Genetic counseling is considered MEDICALLY NECESSARY AND IS REQUIRED (IF TESTING IS NOT BEING ORDERED BY A SPECIALIST IN THE DISEASE PROCESS IN QUESTION (e.g. endocrinologist and maturity onset diabetes of youth gene evaluation)) for individuals prior to and after undergoing genetic testing for diagnostic, carrier, and/or risk assessment purposes.
  2. Genetic testing of the individual's genome for inherited diseases is considered MEDICALLY NECESSARY, once per patient lifetime, when the following criteria are met:
      1. The individual for whom the test is requested is either:
        1. Is currently symptomatic with suspicion of a known genetic disease where knowledge of mutation will assist in diagnosis, treatment, or procreative management, OR
        2. Is currently asymptomatic but is judged to be at significant risk for an inherited disorder or cancer risk factor based on family history and/or ethnicity, AND, if being tested for risk of an adult-onset condition is at or above the age of majority, (e.g., 18 years), unless there is documented evidence that early intervention during childhood may prevent disease severity or time of disease onset, OR
        3. Is asymptomatic but judged to be at risk as a carrier of an inherited disorder or cancer risk factor based on family history and/or ethnicity AND would benefit from procreative management
      2. Regarding the test being considered ALL of the following are MET:
        1. Scientific literature shows association of specific a gene mutation (or mutations) is associated with the disease in question and is clinically actionable (there is clinical utility) with non-investigational treatment; AND
        2. Other testing for the disease is equivocal or does not exist and confirmation of gene mutation is standard of care for the disease state; AND
        3. Disease in question is associated with significant morbidity and/or mortality; AND 
        4. Results of testing can impact clinical management via surveillance or treatment strategies and will guide decisions on healthcare management to mitigate symptoms or progression of the disorder.
  3. Germline multi-gene panel testing (See Note 1), defined as multiple gene tests for a medical condition or symptoms/non-specific presentation run on one testing platform, is considered MEDICALLY NECESSARY according to the guidelines in the preceding coverage criteria and the reimbursement limitations (see section regarding Reimbursement below).

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

  1. Genetic testing of an individual’s genome for inherited diseases is considered NOT MEDICALLY NECESSARY in the following situations: 
        1. For risk assessment of an individual’s genome when the criteria defined in the MCC criteria above are not met
        2. For inherited disease diagnosis or carrier assessment using panels of genes that include genes outside of those specifically related to the disease being investigated
        3. Repeat germline testing of a unique gene using the identical method of gene analysis
        4. Testing as a screening tool in the general population
        5. Direct-to-consumer genetic testing (e.g. mail order, online ordering, pharmacy, retail)

Note 1:  For references regarding the clinical application of genomic sequencing and for appropriate medical coding, please refer to (ACMG, 2012; AMA, 2021).

Reimbursement 

  1. If a procedure code is available for the multi-gene panel test, then this code is to be utilized (i.e. 81442 Noonan spectrum disorders genomic sequence analysis panel).
  2. If there is not a specific next generation sequencing procedure code that represents the requested test, the procedure may be represented by a maximum of ONE unit of 81479 [unlisted molecular pathology procedure] (i.e. 81479 X 1 should account for all remaining gene testing) OR All genes tested on the panel must be represented by ALL appropriate Molecular Pathology Tier 1 or 2 procedure codes (with exception of 81479 x 1 only being listed once if it appropriately represents more than one gene in the panel)
  3. ALL gene tests in the panel must be listed on the request and rationale for the clinical utility for the gene test must come from the ordering provider.
  4. If ALL codes that represent the testing of the panel are not submitted, the test will be denied as not medically necessary due to incorrect coding process as neither laboratory or clinical reviewer should assign meaning to incomplete unspecified panel codes.

Rationale 
Gene mutations are referred to as “germline” if they are within gametes (ova and sperm). Therefore, these mutations may be passed on from parent to offspring (Raby & Blank, 2020). There are many different types of germline mutations, such as single nucleotide polymorphisms (SNPs), structural variations such as deletions, inversions, or translocations, as well as smaller chromosomal abnormalities such as short tandem repeats, or gene fusions. Mutations may not necessarily result in disease (Christensen, 2020; Raby, 2019).

SNPs are the most common type of genetic mutation, such as missense mutations. These mutations are single base-pair changes where one nucleotide is replaced with a different nucleotide. Millions of individual SNPs have been identified through genome-wide association studies, with approximately 4,000 SNPs with potential association with disease (Attia, 2020). Insertion/deletion (indel) polymorphisms are often a single nucleotide but may be up to four nucleotides. SNPs often lead to frameshift mutations, which can cause premature stop codons and the failure of the allele (Raby, Kohlmann, & Venne, 2020).

Structural variations are usually classified as larger than 1,000 base pairs. These include deletions, duplications, inversions, translocations, or ring chromosome formation. Due to the large number of bases affected, these variations may lead to severe genetic abnormalities. For example, a major cause of Duchenne muscular dystrophy is the deletion of large portions of exons (coding portions of genes). The most common structural variation is the copy number variant (CNV), which refers to differing amounts of DNA segments in different individuals. For example, one person may have three copies of a specific segment whereas another may only have two. These variations may lead to dysregulation, gain-of-function, or loss-of-function of the affected genes. The sensitive genes that require or produce precise amounts of a protein product tend to suffer more from these variations (Bacino, 2019a).

Germline mutations are unique in that the risk for certain conditions, including many forms of cancer, may be passed from parent to offspring. Testing for these conditions will often involve testing entire families if one member is found to have a germline mutation; for example, the National Comprehensive Cancer Network (NCCN) guidelines for hereditary cancer recommend testing for BRCA1/2, CDH1, PALB2, PTEN and TP53 mutations if any blood relative has a known or likely pathogenic variant in a cancer susceptibility gene (NCCN, 2020a). Wilson et al. (2020) estimate that 21,800 adult survivors of childhood cancer in the United States carry a pathogenic or likely pathogenic variant in one of 156 cancer predisposition genes. 

Other types of mutations are unique to germline mutations. Errors in chromosome number (aneuploidy) are typically caused by nondisjunctions in meiosis, causing either a monosomic (one chromosome) or a trisomic (three chromosomes) set of chromosomes. Some aneuploidies, trisomy 21 or Down’s Syndrome being most notable, are compatible with life. Aneuploidies may also result with sex chromosomes, resulting in conditions such as Turner’s Syndrome (one X chromosome) or Klinefelter’s Syndrome (XXY) (Bacino, 2019b; Raby, 2019; Schrijver, 2019).

Any size mutation may be pathogenic and must be classified as to how likely they are to cause disease. The American College of Medical Genetics (ACMG) has classified mutations in five categories, which are as follows: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. The “likely pathogenic” and “likely benign” refer to weaker evidence than their respective pathogenic and benign categories, and “uncertain significance” refers to evidence that does not meet criteria for benignity or pathogenicity or has conflicting evidence from both sides (Christensen, 2020; Raby, 2019). Prediction algorithms have been used to interpret variants and to predict whether a variant will affect the gene function or splicing of the gene. These algorithms are publicly available but have a tendency of predicting harmful impact of a variant. The specificity of these databases has been estimated at 60-80% (Li et al., 2017).

Due to the enormous number of variants, as well as the rate that variants are discovered, comprehensive databases of genetic variants have been published and are easily available. For example, the Haplotype Reference Consortium contains over 40 million identified SNPs (Christensen, 2020). Databases focusing on cancer-specific variants, reference sequences, and the general population are all available publicly (Li et al., 2017).

For many years, single-gene testing was the standard approach for germline mutation testing. In recent years, multigene panel testing (MGPT) has been introduced and widely accepted as the first-tier test. MGPT increases the probability of identifying pathogenic mutations and represents an affordable application of next-generation sequencing (NGS) into clinical practice.  However, the clinical utility of MGPT is not well established, especially in cases where more than one pathogenic variant is identified. The risk for a specific malignancy is complex and if a gene panel discovers a mutation incidentally, management can be difficult. Many guidelines call for radical procedures for these disease states and it may cause unnecessary harm for the patient concerned about predisposition to the disease.  Additionally, a combination of mutations may interact to alter the profile of the disease. For instance, certain combinations of mutations may be detrimental and increase the overall risk of cancer malignancy, while other combinations may reduce overall risk of malignancy. In this regard, identifying clinically actionable mutations may be unclear with MGPT (Slaught et al., 2021).

Clinical Validity and Utility
Genetic testing for germline mutations “can be conducted on virtually any tissue type,” although many laboratories prefer blood samples, check swabs or saliva samples (Raby, Kohlmann, & Hartzfeld, 2020). Advancements in technology and availability of sequencing, previously constrained by limitations of sequential single-gene testing on limited patient samples, have led to significant strides in the understanding of the genetic basis of inherited and somatic conditions.

Variants detected by genetic testing include inherited germline variants and somatic mutations; next generation sequencing (NGS) has allowed for superior detection for these mutations (Konnick & Pritchard, 2016). The accuracy of NGS varies depending on how many genes are sequenced; fewer genes tends to result in higher accuracy since there will be more “probe-template overlap.” Although Sanger sequencing remains the most accurate at >99.99% accuracy, it cannot sequence a large quantity of genes in a timely fashion and is best used for sequencing of a specific gene (Hulick, 2020). Pogoda et al. (2019) identified rare variants in the ATM gene by using single molecule Molecular Inversion Probes (smMIPSs), an NGS-based screening method. A total of 373 patients with dystonia and six positive controls with previously identified ATM variants participated in this study. Results generated by the smMIPs “produced similar results as routinely used NGS-based approaches” (Pogoda et al., 2019). This suggests that ATM screening should be routinely used when genetic testing dystonia patients. Further, smMIPs may be an important technique for the germline screening for all rare neurodegenerative disorders.

The clinical validity of a genetic test depends primarily on the expressivity and penetrance of a given phenotype. Penetrance refers to the likelihood of developing a disease when the pathogenic mutation is present, and expressivity refers to the variations in the way the disease is expressed. For example, virtually any mutation in the APC gene will cause symptoms of familial adenomatous polyposis, thereby increasing the clinical validity of an APC assessment while other conditions may not clinically manifest at all despite a mutated genotype (Raby, Kohlmann, & Venne, 2020).

The clinical utility of a genetic test generally relies on available treatments for a condition. Conditions such as Huntington Disease that do not have many options for treatment will have limited clinical utility compared to another condition even though the actual test is highly valid. Factors, such as severity of the disease and management options, affect the clinical utility of a genetic test (Raby, Kohlmann, & Venne, 2020).

American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) (Richards et al., 2015)
The ACMG and AMP released criteria on the types and severity of mutations, which are as follows:

  • Very strong evidence of pathogenicity: Null variants (nonsense, frameshifts, canonical +/- 1-2 splice sites, initiation codon, exon deletions) in a gene where loss of function (LOF) is a known mechanism of disease. The guidelines note to use caution in genes where LOF is not a mechanism, if LOF variants are at the 3’ end, if exon skipping occurs, and if multiple transcripts are present.
  • Strong: Amino acid change to a pathogenic version, de novo mutations, established studies supporting a damaging gene or gene product, or if the prevalence of the variant is increased in affected individuals compared to healthy controls. The guidelines note to be careful of changes impacting splicing and if only the paternity has been confirmed.
  • Moderate: Located in a mutational hot spot or well-established functional domain (e.g., active site of an enzyme) without a benign variation, absent from controls in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium, detected in trans with pathogenic variants for a recessive disorder, protein length changes, novel missense changes where a different missense change has been pathogenic before, and a possible de novo mutation.
  • Supporting: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease, missense variant in a gene with low rate of benign missense variation, if the mutation has evidence that it is deleterious, or if the patient’s phenotype is highly specific for disease with a single genetic cause.

The guidelines also list criteria for benign gene variants.

  • Stand-alone evidence of benignity: Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
  • Strong: Allele frequency is greater than expected for disorder, observed in healthy adult with full penetrance at early age, lack of segregation in affected family members (although pathogenic variants may masquerade as nonsegregated), or well-established studies that show no damaging effect on protein production.
  • Supporting: Missense variant of a gene for which truncating mutations are pathogenic, indels in repetitive region of unknown function, silent variants, variants of unknown significance, or a trans version of a cis mutation (Richards et al., 2015).

National Comprehensive Cancer Network (NCCN) (NCCN, 2018, 2020b, 2021)
Multiple germline mutations have been incorporated into the diagnostic workups recommended by the NCCN. Furthermore, the NCCN has several guidelines which recommend that gene expression profiling, or multiple gene testing, may be helpful, more efficient and/or cost-effective for selected patients (NCCN, 2021). Please see the individual policies.

Association for Molecular Pathology (AMP), American Society of Clinical Oncology (ASCO), and College of American Pathologists (CAP) (Li et al., 2017)
The Joint Commission noted that germline variants should focus on the pathogenicity of a given variant rather than their impact on clinical care. The guidelines recommend reporting germline variants with known clinical impact, such as BRCA1 or 2. A genetic counseling recommendation should also be provided if a pathogenic germline mutation is found.

The guidelines note that it is critical to identify a somatic vs a germline mutation as the type of mutation may have significant clinical consequences (Li et al., 2017).

American Society of Clinical Oncology (ASCO) (Konstantinopoulos et al., 2020; Robson et al., 2015)
The ASCO published guidelines regarding genetic and genomic testing for cancer susceptibility. These guidelines state that the “ASCO recognizes that concurrent multigene testing (i.e., panel testing) may be efficient in circumstances that require evaluation of multiple high-penetrance genes of established clinical utility as possible explanations for a patient’s personal or family history of cancer. Depending on the specific genes included on the panel employed, panel testing may also identify mutations in genes associated with moderate or low cancer risks and mutations in high-penetrance genes that would not have been evaluated on the basis of the presenting personal or family history… ASCO affirms that it is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient’s personal and/or family history (Robson et al., 2015).”

ASCO released guidelines regarding germline testing for ovarian cancer. ASCO recommends that “all women diagnosed with epithelial ovarian cancer should be offered germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes, irrespective of their clinical features or family cancer history. In addition, “first- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene mutation or variant should be offered individualized genetic risk evaluation, counseling, and genetic testing.” Lastly, “clinical decisions should not be based on a variant of uncertain significance (VUS).” In this case, the patient’s clinical features and family history should be taken into consideration and should inform clinical decision making (Konstantinopoulos et al., 2020).

References  

  1. ACMG. (2012). Points to consider in the clinical application of genomic sequencing. Genet Med, 14(8), 759-761. doi:10.1038/gim.2012.74
  2. AMA. (2021). CPT/Current Procedural Terminology (Professional Edition): American Medical Association.
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Coding Section 

Codes Numbers Description
CPT  81105  Human Platelet Antigen 1 genotyping (HPA-1), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa], antigen CD61 [GPIIIa]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-1a/b (L33P)
  81106  Human Platelet Antigen 2 genotyping (HPA-2), GP1BA (glycoprotein Ib [platelet], alpha polypeptide [GPIba]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-2a/b (T145M)  
  81107  Human Platelet Antigen 3 genotyping (HPA-3), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/IIIa complex], antigen CD41 [GPIIb]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-3a/b  (I843S)
  81108  Human Platelet Antigen 4 genotyping (HPA-4), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa], antigen CD61 [GPIIIa]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-4a/b  (R143Q)
  81109  Human Platelet Antigen 5 genotyping (HPA-5), ITGA2 (integrin, alpha 2 [CD49B, alpha 2 subunit of VLA-2 receptor] [GPIa]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common  variant (eg, HPA-5a/b (K505E))
  81110  Human Platelet Antigen 6 genotyping (HPA-6w), ITGB3 (integrin, beta 3 [platelet glycoprotein IIIa, antigen CD61] [GPIIIa]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-6a/b (R489Q) 
  81111  Human Platelet Antigen 9 genotyping (HPA-9w), ITGA2B (integrin, alpha 2b [platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41] [GPIIb]) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-9a/b (V837M) 
  81112  Human Platelet Antigen 15 genotyping (HPA-15), CD109 (CD109 molecule) (eg, neonatal alloimmune thrombocytopenia [NAIT], post-transfusion purpura), gene analysis, common variant, HPA-15a/b (S682Y) 
  81161 DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis if performed 
  81173 (effective 01/01/2019)  AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence 
  81174 (effective 01/01/2019)  AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; known familial variant 
  81177 (effective 01/01/2019)  ATN1 (atrophin 1) (eg, dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81178 (effective 01/01/2019)  ATXN1 (ataxin 1) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81179 (effective 01/01/2019)  ATXN2 (ataxin 2) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81180 (effective 01/01/2019)  ATXN3 (ataxin 3) (eg, spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81181 (effective 01/01/2019)  ATXN7 (ataxin 7) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81182 (effective 01/01/2019)  ATXN8OS (ATXN8 opposite strand [non-protein coding]) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81183 (effective 01/01/2019)  ATXN10 (ataxin 10) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81187 (effective 01/01/2019)  CNBP (CCHC-type zinc finger nucleic acid binding protein) (eg, myotonic dystrophy type 2) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81188 (effective 01/01/2019)  CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles 
  81189 (effective 01/01/2019)  CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; full gene sequence 
  81190 (effective 01/01/2019)   CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; known familial variant(s) 
  81204 (effective 01/01/2019)  AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (eg, expanded size or methylation status) 
  81228 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) 
  81229 Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities 
  81233 (effective 01/01/2019)  BTK (Bruton's tyrosine kinase) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, C481S, C481R, C481F) 
  81234 (effective 01/01/2019)  DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles 
  81236 (effective 01/01/2019)  EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, myelodysplastic syndrome, myeloproliferative neoplasms) gene analysis, full gene sequence 
  81237 (effective 01/01/2019)  EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, diffuse large B-cell lymphoma) gene analysis, common variant(s) (eg, codon 646) 
  81238 (effective 1/1/2018) F9 (coagulation factor IX) (eg, hemophilia B), full gene sequence 
  81239 (effective 01/01/2019)  DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; characterization of alleles (eg, expanded size) 
  81247 (effective 1/1/2018) G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; common variant(s) (eg, A, A-) 
  81248 (effective 1/1/2018)  G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; known familial variant(s) 
  81249 (effective 1/1/2018) G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; full gene sequence 
  81252 GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence 
  81260 IKBKAP (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein) (eg, familial dysautonomia) gene analysis, common variants (eg, 2507+6T>C, R696P) 
  81271 (effective 01/01/2019)  HTT (huntingtin) (eg, Huntington disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles 
  81274 (effective 01/01/2019)  HTT (huntingtin) (eg, Huntington disease) gene analysis; characterization of alleles (eg, expanded size) 
  81283 (effective 1/1/2018) IFNL3 (interferon, lambda 3) (eg, drug response), gene analysis, rs12979860 variant 
  81284 (effective 01/01/2019)  FXN (frataxin) (eg, Friedreich ataxia) gene analysis; evaluation to detect abnormal (expanded) alleles 
  81285 (effective 01/01/2019)  FXN (frataxin) (eg, Friedreich ataxia) gene analysis; characterization of alleles (eg, expanded size) 
  81286 (effective 01/01/2019)  FXN (frataxin) (eg, Friedreich ataxia) gene analysis; full gene sequence 
  81289 (effective 01/01/2019)  FXN (frataxin) (eg, Friedreich ataxia) gene analysis; known familial variant(s) 
  81305 (effective 01/01/2019)  MYD88 (myeloid differentiation primary response 88) (eg, Waldenstrom's macroglobulinemia, lymphoplasmacytic leukemia) gene analysis, p.Leu265Pro (L265P) variant 
  81307 (effective 01/01/2020) 

PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence

  81308 (effective 01/01/2020)  

PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant

  81312 (effective 01/01/2019)  PABPN1 (poly[A] binding protein nuclear 1) (eg, oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81320 (effective 01/01/2019)   PLCG2 (phospholipase C gamma 2) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, R665W, S707F, L845F) 
  81329 (effective 01/01/2019)  SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; dosage/deletion analysis (eg, carrier testing), includes SMN2 (survival of motor neuron 2, centromeric) analysis, if performed 
  81333 (effective 01/01/2019)  TGFBI (transforming growth factor beta-induced) (eg, corneal dystrophy) gene analysis, common variants (eg, R124H, R124C, R124L, R555W, R555Q) 
  81336  SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; full gene sequence 
  81337 SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; known familial sequence variant(s) 
  81343 (effective 01/01/2019)  PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81344 (effective 01/01/2019)  TBP (TATA box binding protein) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 
  81400

 Molecular pathology procedure, Level 1

Genes: ACADM, ACE, AGTR1, BCKDHA, CCR5, CLRN1, DPYD, F2, F5, F7, F13B, FGB, FGFR1, FGFR3, FKTN, GNE, Human Platelet Antigen 1 genotyping, Human Platelet Antigen 2 genotyping, Human Platelet Antigen 3 genotyping, Human Platelet Antigen 4 genotyping, Human Platelet Antigen 5 genotyping, Human Platelet Antigen 6 genotyping, Human Platelet Antigen 9 genotyping, Human Platelet Antigen 15 genotyping, IL28B, IVD, LCT, NEB, PCDH15, SERPINE1, SHOC2, SMN1, SRY, TOR1A 
  81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)

Genes: ABCC8, ABL1, ACADM, ADRB2, AFF2, APOB, APOE, AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, ATXN8OS, ATXN10, CACNA1A, CBFB/MYH11, CBS, CCND1/IGH, CFH/ARMS2, CNBP, CSTB, CYP3A4, CYP3A5, DEK/NUP214, DMPK, E2A/PBX1, EML4/ALK, ETV6/NTRK3, ETV6/RUNX1, EWSR1/ATF1, EWSR1/ERG, EWSR1/FLI1, EWSR1/WT1, F11, FIP1L1/PDGFRA, FLG,FOXO1/PAX3, FOXO1/PAX7, FUS/DDIT3, FXN, GALC, GALT, H19, HBB, HTT, IGH@/BCL2 (When both MBR and mcr breakpoints are performed, use 81402), KCNQ1OT1, LRRK2, MED12, MEG3/DLK1, MLL/AFF1, MLL/MLLT3, MT-ATP6, MT-ND4, MT-ND5,MT-RNR1, MT-TK, MT-TL1, MT-TS1, MT-RNR1, MUTYH, NOD2, NPM1/ALK, PABPN1, PAX8/PPARG, PPP2R2B, PRSS1, PYGM, RUNX1/RUNX1T1, SMN1/SMN2 (For duplication/deletion analysis of MN1/SMN2, use 81401)SS18/SSX1, SS18/SSX2, TBP, TPMT, TYMS, VWF 
  81402

 Molecular pathology procedure, Level 3

Genes: Chromosome 1p-/19q-, Chromosome 18q, COL1A1/PDGFB, CYP21A2, ESR1/PGR, IGH@/BCL2, MEFV, MPL, TRD@, Uniparental disomy (UPD) 
  81403

Molecular pathology procedure, Level 4

Genes: ANG, ARX, CEL, CTNNB1, DAZ/SRY, DNMT3A, EPCAM, F8, F12, FGFR3 (For targeted sequence analysis of multiple FGFR3 exons, use 81404), GJB1, GNAQ, HBB,Human erythrocyte antigen gene analyses, HRAS, IDH1, IDH2, JAK2, Killer cell immunoglobulin-like receptor (KIR) gene family, Known familial variant not otherwise specified, for gene listed in Tier 1 or Tier 2, or identified during a genomic sequencing procedure, DNA sequence analysis, each variant exon (For a known familial variant that is considered a common variant, use specific common variant Tier 1 or Tier 2 code), KCNC3, KCNJ2, CNJ11, MC4R,MICA, MPL, MT-RNR1, MT-TS1, NDP, NHLRC1, PHOX2B,PLN, RHD (For human erythrocyte gene analysis of RHD, use a separate unit of 81403), SH2D1A, SMN1, TWIST1, UBA1, VHL, VWF 
  81404

Molecular pathology procedure, Level 5

Genes: ACADS, AFF2, AQP2, ARX, AVPR2, BBS10, BTD, C10orf2, CAV3, CD40LG, CDKN2A, CLRN1, COX6B1, CPT2, CRX, CSTB, CYP1B1, DMPK, GR2, EPM2A, FGF23, FGFR2, FGFR3,FHL1, FKRP, FOXG1, FSHMD1A, FSHMD1A, FXN, GP1BB, HBA1/HBA2 (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257), HBB, HNF1B, HRAS, HSD3B2, HSD11B2, HSPB1, KCNJ1, KCNJ10, LITAF, MEFV, MEN1, MMACHC, MPV17, NDUFA1, NDUFAF2, NDUFS4, NIPA1, NLGN4X, NPC2, PDX1, PHOX2B, PIK3CA, PLP1, PQBP1, PROP1, PRPH2, PRSS1, RAF1, RET,RHO, SCN1B, SCO2, SDHC, SDHD, SGCG, SH2D1A, SLC16A2, SLC25A20, SLC25A4, SOD1, SPINK1, STK11, TACO1, THAP1, TOR1A, TP53, TTPA, TTR, TWIST1, TYR, USH1G, VHL, VWF, ZEB2, ZNF41 
  81405

Molecular pathology procedure, Level 6

Genes:  ABCD1, ACTA2, ACTC1, ANKRD1, APTX, ARSA, BCKDHA, BCS1L, BMPR2, CASQ2, CASR, CDKL5, CHRNA4, CHRNB2, COX10, COX15, CYP11B1, CYP17A1, Cytogenomic constitutional targeted microarray analysis of chromosome 22q13 by interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities, CYP21A2, DBT, DCX, DFNB59, DGUOK, DHCR7, EIF2B2, EMD, ENG, EYA1, F9, GFR1, FKTN, FTSJ1, GABRG2, GCH1, GDAP1, GFAP, GHR, GHRHR, GLA, HBA1/HBA2, HNF1A, HNF1B, HTRA1, IDS, IL2RG, ISPD, KRAS, LAMP2, LDLR, MEN1, MMAA, MMAB, MPI, MPV17, MPZ, MTM1, MYL2, MYL3, MYOT, NDUFS7, NDUFS8, NDUFV1, NEFL, NF2, NLGN3, NLGN4X, NPHS2, NSD1, OTC, PAFAH1B1, PARK2, PCCA, PCDH19, PDHA1, PDHB, PINK1, PLP1, POU1F1, PRX, PQBP1, PSEN1, RAB7A, RAI1, REEP1, RET, RPS19, RRM2B, SCO1, SDHB, SDHC, SGCA, SGCB, SGCD, SGCE, SGCG, SHOC2, SIL1, SLC2A1, SLC16A2, SLC22A5, SLC25A20, SMAD4,SMN1, SPAST, SPRED, STAT3, STK11, SURF1, TARDBP, TBX5, TCF4, TGFBR1, THRB, TK2, TNNC1, TNNI3, TP53, TPM1, TSC1, TYMP, VWF, WT1, ZEB2 
  81406

Molecular pathology procedure, Level 7

Genes:  ACADVL, ACTN4, AFG3L2, AIRE, ALDH7A1, ANO5, APP, ASS1, ATL1, ATP1A2, ATP7B, BBS1, BBS2, BCKDHB, BEST1, BMPR2, BRAF,BSCL2, BTK, CACNB2, CAPN3, CBS, CDH1, CDKL5, CLCN1, CLCNKB, CNTNAP2, COL6A2, CPT1A, CRB1, CREBBP, Cytogenomic microarray analysis, neoplasia, DBT, DLAT, DLD, DSC2, DSG2, DSP, EFHC1, EIF2B3, EIF2B4, EIF2B5, ENG, EYA1, F8, FAH, FASTKD2, FIG4, FTSJ1, FUS, GAA, GALC, GALT, GARS, GCDH, GCK, GLUD1, GNE, GRN, HADHA, HADHB, HEXA, HLCS, HNF4A, IDUA, INF2, IVD, JAG1, JUP, KAL1, KCNH2, KCNQ1, KCNQ2, LDB3, LDLR, LEPR, LHCGR, LMNA, LRP5, MAP2K1, MAP2K2, MAPT, MCCC1, MCCC2, MFN2, MTM1, MUT, MUTYH, NDUFS1, NF2, NOTCH3, NPC1, NPHP1, NSD1, OPA1, OPTN, PAFAH1B1, PAH, PALB2, PARK2, PAX2, PC, PCCA, PCCB, PCDH15, PCSK9, PDHA1, PDHX, PHEX, PKD2, PKP2, PNKD, POLG, POMGNT1, POMT1, POMT2, PRKAG2, PRKCG, PSEN2, PTPN11, PYGM, RAF1, RET, RPE65, RYR1, SCN4A, SCNN1A, SCNN1B, SCNN1G, SDHA, SETX, SGCE, SH3TC2, SLC9A6, SLC26A4, SLC37A4, SMAD4, SOS1, SPAST, SPG7, STXBP1, TAZ, TCF4, TH, TMEM43, TNNT2, TRPC6, TSC1, TSC2, UBE3A, UMOD, VWF, WAS 
  81407

Molecular pathology procedure, Level 8

Genes:  ABCC8, AGL, AHI1, ASPM, CACNA1A, CHD7, COL4A4, COL4A5, COL6A1, COL6A2, COL6A3, CREBBP, F8, JAG1, KDM5C, KIAA0196, L1CAM, LAMB2, MYBPC3, MYH6, MYH7, MYO7A, NOTCH1, NPHS1, OPA1, PCDH15, PKD1, PLCE1, SCN1A, SCN5A, SLC12A1, SLC12A3, SPG11, PTBN2, TMEM67, TSC2, USH1C, VPS13B, WDR62 
  81408

Molecular pathology procedure, Level 9

Genes:  ABCA4, ATM, CDH23, CEP290, COL1A1, COL1A2, COL4A1, COL4A3, COL4A5, DMD, DYSF, FBN1, ITPR1, LAMA2, LRRK2, MYH11, NEB, NF1, PKHD1, RYR1, RYR2, USH2A, VPS13B, VWF 
  81442 

Noonan spectrum disorders (eg, Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, LEOPARD syndrome, Noonan-like syndrome), genomic sequence analysis panel, must include sequencing of at least 12 genes, including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1 

  81443 (effective 01/01/2019) Genetic testing for severe inherited conditions (eg, cystic fibrosis, Ashkenazi Jewish-associated disorders [eg, Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (eg, ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH) 
  81470  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 SLC16A2 
  81471  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 SLC16A2 
  81479 Unlisted molecular pathology procedure (only 1 unit of service) 
  S3840 DNA analysis for germline mutations 
HCPCS  0130U  BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) mRNA sequence analysis (List separately in addition to code for primary procedure) 
  0138U  BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) mRNA sequence analysis (List separately in addition to code for primary procedure)
Proprietary test: RNAinsight™ for BRCA1/2
Lab/Manufacturer: Ambry Genetics
  0230U  AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation), full sequence analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non-uniquely mappable regions
Proprietary test: Genomic Unity® AR Analysis
Lab/Manufacturer: Variantyx Inc
 
  0232U  CSTB (cystatin B) (eg, progressive myoclonic epilepsy type 1A, Unverricht-Lundborg disease), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, short tandem repeat (STR) expansions, mobile element insertions, and variants in non-uniquely mappable regions
Proprietary test: Genomic Unity® CSTB Analysis
Lab/Manufacturer: Variantyx Inc
 
  0236U  SMN1 (survival of motor neuron 1, telomeric) and SMN2 (survival of motor neuron 2, centromeric) (eg, spinal muscular atrophy) full gene analysis, including small sequence changes in exonic and intronic regions, duplications and deletions, and mobile element insertions
Proprietary test: Genomic Unity® SMN1/2 Analysis
Lab/Manufacturer: Variantyx Inc
 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2017 Forward     

04/01/2021 

Annual review, no change to policy intent. Updating description, rationale, references and coding. 

06/16/2020 

Interim review, updating coding. No change to policy intent. 

04/13/2020 

Annual review, no change to policy intent. Updating coding. 

01/06/2020 

Interim review to update coding. No other changes made. 

12/13/2019 

 Added codes '81227, 81307, 81308', and '81309'

07/16/2019 

Updating the coding section with codes 81336 and 81337. No other changes. 

07/01/2019 

Interim review. Adding Reimbursement section to policy. 

05/10/2019 

Updating verbiage regarding genetic counseling for specificity.

04/03/2019 

Annual review, adding policy statement #3 regarding germline multi gene panel testing. No other changes to policy intent. Also updating coding. 

12/21/2018 

Updated with additional 2019 codes.  

12/18/2018 

Updating policy with 2019 codes. 

04/28/2018 

Annual review. updating cpt coding. no change to policy intent. 

12/7/2017 

Updating policy with 2018 coding. No other changes.

04/24/2017 

Updating Category to Laboratory. 

04/06/2017

New Policy


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