This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Hereditary Cancer Syndrome Multigene Panels may be considered medical necessary when the following clinical criteria are met.

This policy applies to all hereditary cancer syndrome panels, which are defined as assays that simultaneously test for more than one hereditary cancer syndrome. This policy does not apply when testing more than one gene related to the same hereditary cancer syndrome (e.g., Lynch syndrome).

Medical necessity coverage generally relies on criteria established for testing individual hereditary cancer syndromes. See Tables 1 and 2 for examples of genes known to be included in currently available hereditary cancer syndrome multi-gene panels with coverage guidance. This is not intended to be a complete list of available genes as these panels are evolving rapidly.

However, this policy takes into account the efficiency gains from simultaneously testing multiple candidate genes. Therefore, coverage requirements rely to some degree on how the panel will be billed. Panels may be billed in a variety of ways:

• Gene sequencing portion:
  • A separate CPT code for sequencing each gene studied or a subset (e.g., 81201, 81294, 81297, etc.)
  • A single CPT code developed specifically for a particular type of panel (e.g., 81432, 81435, 81437)
  • A single unlisted CPT code (e.g., 81479)
• Deletion/duplication analysis portion:
  • A separate CPT code for deletion/duplication analysis of each gene studied or a subset (e.g., 81203, 81292, 81294, 81404, 81479, etc.)
  • A single CPT code developed specifically for a particular type of panel (e.g., 81433, 81436, 81438)
  • Microarray analysis (e.g., 81228 or 81229
  • Part of a single unlisted CPT code for the sequencing and deletion/duplication portions of the panel (e.g., 81479)

Hereditary cancer syndrome multi-gene panels may be considered medically necessary when the following criteria are met:

• Panel will be billed with separate procedure codes for each gene analyzed (however, please note that the billed amount should not exceed the list price of the test).
  • The medical necessity of each billed procedure will be assessed independently. See Tables 1 and 2 below for gene-specific policy guidance.
    • When a patient meets medical necessity criteria for any hereditary cancer syndrome gene(s) included in a multi-gene panel, genetic testing for the clinically indicated gene(s) will be covered. This includes the sequencing and deletion/duplication* components.
    • Any genes that are included in a multi-gene panel but do NOT meet medical necessity criteria will NOT be a covered service. It will be at the laboratory, provider, and patient’s discretion to determine if a multi-gene panel remains the preferred testing option.
  • Sequencing and/or deletion/duplication analysis* of any hereditary cancer syndrome gene(s) should only be performed once per lifetime and will therefore only be covered once (1) per lifetime. If gene testing was previously performed, and is now being included in a panel, such testing will not be separately reimbursable regardless of whether clinical coverage criteria are met; or
• Panel will be billed with a single procedure code to represent all genes being sequenced, with or without another single procedure code representing the deletion/duplication analysis* portion. Code(s) may be specific to that panel or an unlisted code, such as 81479.
  • No previous hereditary cancer syndrome testing has been performed.
    • Medical necessity must be established for at least two (2) conditions included in the panel (e.g., hereditary breast and ovarian cancer and Li Fraumeni syndrome). Note that this is two conditions and not two genes (i.e., meeting criteria for only Lynch syndrome, which is caused by mutations in at least 5 genes, would not fulfill criteria alone).
  • Testing for one (1) condition was performed and billed separately. A multigene panel is now being considered as a reflex and will be billed at a rate comparable to single syndrome pricing (e.g., myRisk update).
    • Medical necessity must be established for at least one (1) condition included in the panel in addition to the already tested condition (e.g., hereditary breast and ovarian cancer was already performed, but Lynch syndrome criteria are also met).

*When deletion/duplication testing is not part of a single panel CPT code being billed, deletion/duplication testing should be billed in only one of the following ways:

• A separate CPT code for deletion/duplication analysis of each individual gene (may include non-specific molecular pathology tier 2 codes or unlisted code 81479); or
• A single CPT code specific to the performed deletion/duplication analysis panel; or
• A single microarray procedure.

Procedure codes representing multiple methods for deletion/duplication testing will not be reimbursable for the same panel (e.g., test-specific deletion/duplication procedure codes and microarray will not both be reimbursable for the same panel).

When the above criteria are not met, hereditary cancer syndrome multi-gene panels are considered not medically necessary.

For all other indications not listed above in this policy, hereditary cancer syndrome multi-gene panels are considered not medically necessary.

Table 1  Covered Genes Included in Hereditary Cancer Syndrome Multi-Gene Panels 

Condition	Test Name	CPT
Birt-Hogg-Dube syndrome	FLCN Sequencing	81479
	FLCN Deletion/Duplication Analysis	81479
Cowden syndrome, PTEN hamartoma tumor syndrome	PTEN Deletion/Duplication Analysis	81323
	PTEN Sequencing	81321
Cutaneous malignant melanoma	CDK 4 Deletion/Duplication Analysis	81479
	CDK4 Exon 2 Sequencing	81479
	CDKN2A Deletion/Duplication Analysis	81479
	CDKN2A Sequencing	81404
Familial adenomatous polyposis	APC Deletion/Duplication Analysis	81203
	APC Sequencing	81201
Familial Wilms tumor	WT1 Sequencing	81405
Hereditary breast and ovarian cancer	BRCA1/2 Sequencing	81211
	BRCA1/2 Deletion/Duplication Analysis	81213
	BRCA1 Sequencing	81214
	BRCA2 Sequencing	81216
Hereditary diffuse gastric cancer	CDH1 Sequencing	81406
	CTNNA1 Deletion/Duplication Analysis	81479
	CTNNA1 Sequencing	81479
Hereditary leiomyomatosis with renal cell cancer	FH Sequencing	81405
Hereditary mixed polyposis syndrome, Juvenile polyposis syndrome	BMPR1A Deletion/Duplication Analysis	81479
	BMPR1A Sequencing	81479
Hereditary papillary renal cell carcinoma	MET Sequencing	81479
	MET Deletion/Duplication Analysis	81479
Hereditary paragangliomapheochromocytoma syndromes	SDHA Sequencing	81406
	SDHB Deletion/Duplication Analysis	81479
	SDHB Sequencing	81405
	SDHC Deletion/Duplication Analysis	81404
	SDHC Sequencing	81405
	SDHD Deletion/Duplication Analysis	81479
	SDHD Sequencing	81404
	MAX Sequencing	81479
	MAX Deletion/Duplication Analysis	81479
	SDHAF2 Sequencing	81479
	SDHAF2 Deletion/Duplication Analysis	81479
	TMEM127 Sequencing	81479
	TMEM127 Deletion/Duplication Analysis	81479
Juvenile polyposis syndrome	SMAD4 Deletion/Duplication Analysis	81405
	SMAD4 Sequencing	81406
Li-Fraumeni syndrome	TP53 Deletion/Duplication Analysis	81479
	TP53 Sequencing	81405
	TP53 Targeted Sequencing	81404
Lynch syndrome	EPCAM Deletion/Duplication Analysis	81403
	MLH1 Deletion/Duplication Analysis	81294
	MLH1 Sequencing	81292
	MSH2 Deletion/Duplication Analysis	81297
	MSH2 Sequencing	81295
	MSH6 Deletion/Duplication Analysis	81300
	MSH6 Sequencing	81298
	PMS2 Deletion/Duplication Analysis	81319
	PMS2 Sequencing	81317
Multiple endocrine neoplasia type 1	MEN1 Deletion/Duplication Analysis	81404
	MEN1 Sequencing	81405
Multiple endocrine neoplasia, type 2A	RET Sequencing	81406
	RET Targeted Sequencing	81405
MUTYH-associated polyposis	MUTYH Deletion/Duplication Analysis	81479
	MUTYH Sequencing	81406
Neurofibromatosis type	NF1 Deletion/Duplication Analysis	81479
	NF1 Sequencing	81408
Peutz-Jeghers syndrome	STK11 Deletion/Duplication Analysis	81404
	STK11 Sequencing	81479
von Hippel-Lindau syndrome	VHL Deletion/Duplication Analysis	81403
	VHL Sequencing	81404

Table 2   Not Covered Genes Included in Hereditary Cancer Syndrome Multi-Gene Panels

The following Gene testing is not covered strictly for hereditary cancer indication. In general, this category applies to genes that have only a low to moderate impact on cancer risk (compared to high penetrance cancer syndrome-causing genes) and no clear management guidelines associated with identifying a mutation.

Condition	Test Name	CPT
Tumor Predisposition Syndrome	BAP1 Deletion/Duplication Analysis	81479
	BAP 1 Sequencing	81479
Unknown Phenotype	CHEK1 Deletion/Duplication Analysis	81479
	CHEK1 Sequencing	81479
	RAD51B Deletion/Duplication Analysis	81479
	RAD15B Sequencing	81479
Von Hippel-Lindau Syndrome	VHL Deletion/Duplication Analysis	81403
	VHL Sequencing	81404
Familial breast and/or ovarian cancer	AKT1 Deletion/Duplication Analysis	81479
	AKT1 Sequencing	81479
	ATM Deletion/Duplication Analysis	81479
	ATM Sequencing	81408
	BARD1 Deletion/Duplication Analysis	81479
	BARD1 Sequencing	81479
	BRIP1 Deletion/Duplication Analysis	81479
	BRIP1 Sequencing	81479
	CHEK2 Deletion/Duplication Analysis	81479
	CHEK2 Sequencing	81479
	FAM175A Deletion/Duplication Analysis	81479
	FAM175A Sequencing	81479
	GEN1 Deletion/Duplication Analysis	81479
	GEN1 Sequencing	81479
	MRE11A Deletion/Duplication Analysis	81479
	MRE11A Sequencing	81479
	NBN Deletion/Duplication Analysis	81479
	NBN Sequencing	81479
	RAD50 Deletion/Duplication Analysis	81479
	RAD50 Sequencing	81479
	RAD51 Deletion/Duplication Analysis	81479
	RAD51 Sequencing	81479
	RAD51C Deletion/Duplication Analysis	81479
	RAD51C Sequencing	81479
	RAD51D Deletion/Duplication Analysis	81479
	RAD51D Sequencing	81479
	SMARCA4 Deletion/Duplication Analysis	81479
	SMARCA4 Sequencing	81479
	XRCC2 Deletion/Duplication Analysis	81479
	XRCC2 Sequencing	81479
	XRCC3 Deletion/Duplication Analysis	81479
	XRCC3 Sequencing	81479
Familial colorectal cancer	AXIN2 Deletion/Duplication Analysis	81479
	AXIN2 Sequencing	81479
	GALNT12 Deletion/Duplication Analysis	81479
	GALNT12 Sequencing	81479
	MLH3 Deletion/Duplication Analysis	81479
	MLH3 Sequencing	81479
	POLE Sequencing	81479
	POLD1 Sequencing	81479
Familial cutaneous telangiectasia and cancer syndrome	ATR Deletion/Duplication Analysis	81479
	ATR Sequencing	81479
Familial pancreatic cancer	PRSS1 Deletion/Duplication Analysis	81479
	PRSS1 Sequencing	81404
Familial prostate cancer	HOXB13 Deletion/Duplication Analysis	81479
	HOXB13 Sequencing	81479
Familial renal cell carcinoma	MITF Sequencing	81479
	MITF Deletion/Duplication Analysis	81479
Hereditary breast and pancreatic cancer	PALB2 Sequencing	81406
Hereditary mixed polyposis syndrome	GREM1 Deletion/Duplication Analysis	81479
	GREM1 Sequencing	81479

Hereditary cancer syndrome multigene panels are typically outpatient procedures which are only eligible for coverage as inpatient procedures in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

A network provider cannot bill the member for the non-covered service.

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