Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Germline Genetic Testing for Pancreatic Cancer Susceptibility Genes

Description:

Pancreatic cancer is the fourth leading cause of cancer death in the U.S., accounting for 7.9% of all cancer deaths in 2021 (NIH, 2019). The disease has a poor prognosis, with only 10.8% of patients surviving to 5 years. Five-year survival for localized pancreatic cancer is 41.6% but most symptomatic patients have advanced, incurable disease at diagnosis.

Approximately 10%-15% of patients with pancreatic cancer are thought to have a hereditary susceptibility to the disease (Stoffel, 2019). Multiple genetic syndromes, including hereditary breast and ovarian cancer syndrome, are associated with an increased risk for pancreatic cancer. Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA or PALB2 variant, with higher rates observed in those with a family or personal history of pancreatic cancer or other BRCA-related malignancies (O’Reilly, 2020). The incidence of germline PALB2 mutations in persons with PDAC is estimated to be between 0.6% and 2.1% (Reiss, 2018).

Having a first-degree relative with pancreatic cancer increases an individual's risk of developing pancreatic cancer, and the degree of risk increases depending on the number of affected relatives (Owens, 2019). Individuals are considered at high-risk for hereditary pancreatic cancer if they have 2 relatives with pancreatic cancer where 1 is a first-degree relative, have 3 or more relatives with pancreatic cancer or have a history of hereditary pancreatitis. In 80% of pancreatic cancer patients with a family history of pancreatic cancer, the genetic basis of the inherited predisposition is unknown (NCCN, 2021).

Germline genetic testing for pancreatic cancer susceptibility genes has several proposed purposes. In patients with pancreatic cancer, the purpose of genetic testing would be to guide treatment decisions (e.g., selection of platinum-based chemotherapy for first-line treatment, targeted treatment with a poly ADP ribose polymerase [PARP] inhibitor). In asymptomatic patients at high risk of pancreatic cancer (e.g., due to family history or other clinical factors), the purpose of genetic testing would be to inform decisions about surveillance for early detection of pancreatic cancer. Because the incidence of pancreatic cancer in the general population is low, with a lifetime risk of approximately 1.6%, screening is not recommended for patients who are not at high-risk, but patients with a family history of pancreatic cancer or a syndrome associated with increased risk of pancreatic cancer are potential targets for surveillance.

Regulatory Status

Testing for variants associated with pancreatic cancer is typically done by direct sequence analysis or next-generation sequencing. Several laboratories offer to test for the relevant genes, either individually or as panels.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Lab Test X is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

In December 2019, the FDA approved olaparib (LYNPARZA, AstraZeneca Pharmaceuticals LP) for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Also in 2019, BRACAnalysis CDx received expanded FDA approval for use as a companion diagnostic for Lynparza (olaparib) in pancreatic cancer patients (FDA, 2019)

Coding

There is no test specifically for pancreatic cancer. For purposes of this policy, the following codes may be billed.

CPT codes for PALB2 testing:

81307 (PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence)
81308 (PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant)

CPT codes for BRCA1 & BRCA2 testing:

81162 BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (ie, detection of large gene rearrangements)
81163 BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81164 BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81165 BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81166 BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81167 BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81211 BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and common duplication/deletion variants in BRCA1 (ie, exon 13 del 3.835kb, exon 13 dup 6kb, exon 14 20 del 26kb, exon 22 del 510bp, exon 8 9 del 7.1kb)
81212 BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants
81215 BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant
81216 BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81217 BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant

Policy/
Coverage:

Effective July 15, 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for BRCA1, BRCA2, and PALB variants to guide selection for treatment with platinum-based chemotherapy in previously untreated patients with locally advanced or metastatic pancreatic cancer meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Genetic testing for BRCA1 and BRCA2 variants to guide selection for treatment with olaparib (Lynparza) in patients with pancreatic cancer meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for BRCA1, BRCA2, and PALB variants to guide selection for treatment of pancreatic cancer not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for BRCA1, BRCA2, and PALB variants to guide selection for treatment of pancreatic cancer not described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Genetic testing for ATM, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 in patients with pancreatic cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for ATM, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 in patients with pancreatic cancer is considered investigational.

Genetic testing for ATM, BRCA1, BRCA2, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 in asymptomatic individuals at high risk for hereditary pancreatic cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, genetic testing for ATM, BRCA1, BRCA2, CDK2NA, EPCAM, MMR genes (MLH1, MSH2, MSH6, PMS2), STK11, and TP53 in asymptomatic individuals at high risk for hereditary pancreatic cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Genetic Testing for a BRCA1, BRCA2, or PALB2 Variant to Select First-Line Treatment

There is no direct evidence from RCTs of the clinical utility of germline testing for BRCA or PALB2 variants in patients with pancreatic cancer. Several retrospective observational studies and an uncontrolled subgroup analysis from a randomized controlled trial of veliparib have reported a survival advantage for pancreatic cancer patients with BRCA or PALB2 pathogenic variants who received platinum-containing chemotherapy.

Golan et al analyzed survival data and clinical characteristics from databases of pancreatic cancer patients treated at 3 institutions between 1994 and 2012, including 71 patients with BRCA1 or BRCA2 variants (Golan, 2014). Longer median overall survival was observed in patients with BRCA variants who received platinum-based chemotherapy compared to those who received non-platinum-based chemotherapies (22 months [range 6–27] vs 9 months [range 4–12]; P =.039).

Three retrospective cohort studies used similar methods to compare survival outcomes in patients with or without BRCA or PALB2 variants who were treated with platinum-based chemotherapy (Wattenberg, 2020; Yu, 2019; Reiss, 2018). In these studies, patients with a pathogenic variant were matched to control patients on prognostic factors such as age at diagnosis, sex, and stage of disease. All of these studies reported a survival advantage when variant-positive patients were treated with platinum vs non-platinum-based regimens, while there was no advantage for platinum-based therapy in patients who did not harbor a BRCA or PALB2 variant.

Major limitations include the studies’ small sample sizes and retrospective designs. The timing of genetic testing varied within the patient cohorts (e.g. some patients were tested before and others after their pancreatic cancer diagnosis). It is possible that patients who survived their PDAC diagnosis longer were more likely to undergo genetic testing. Because many control patients were not tested, some may have been variant-positive. However, this is less of a concern because this would have biased results toward the null. There was also heterogeneity in the timing and type of chemotherapy regimens patients received. Although the studies attempted to control for confounding by matching patients on important prognostic factors or using statistical analysis methods, the potential for unmeasured confounding decreases confidence in the results. Despite these limitations, consistency in the magnitude and direction of results across studies suggest that a strategy of testing for these variants to aid in decision-making about first-line treatment is a reasonable approach.

O’Reilly et al conducted an RCT of platinum-based chemotherapy with or without the PARP inhibitor veliparib in patients with previously untreated, locally advanced or metastatic pancreatic cancer and a BRCA or PALB2 germline variant (O’Reilly,2020). Two-year OS rate for the entire cohort was 30.6%(95%CI, 17.8%to 44.4%), and 3-year OS rate for the entire cohort was 17.8% (95% CI, 8.1% to 30.7%).Overall survival did not differ significantly when veliparib was added to the platinum-based regimen. The trial was not designed to compare platinum-based vs standard chemotherapy, but it does provide uncontrolled evidence of the effectiveness of platinum-containing chemotherapy in patients with germline pathogenic BRCA or PALB2 variants. The major limitation of this analysis was the lack of a control group of patients who did not receive platinum-based chemotherapy.

Genetic Testing for a BRCA1 or BRCA2 Variant to Select Targeted Treatment

Golan et al. conducted a placebo controlled RCT of olaparib as maintenance therapy in patients with germline BRCA1 or BRCA2 variants and metastatic pancreatic cancer (Golan, 2019). Of 3315 patients screened, 247 (7.5%) had a germline BRCA mutation. Median progression-free survival was longer in the olaparib group, but there was no difference in OS.

Genetic Testing for ATM, CDK2NA, EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, and TP53 to Guide Treatment in Individuals with Pancreatic Cancer

Multiple observational studies have demonstrated that testing patients with pancreatic cancer can identify individuals with disease-associated variants; A case-control analysis conducted by Hu et al compared the association of germline pathogenic variations in 3030 patients with pancreatic cancer to 176241 controls from 2 public genome databases (Hu, 2018). There were significant associations between pancreatic cancer and pathogenic variations in 6 genes associated with pancreatic cancer (ATM, BRCA1, BRCA2, CDKN2A, MLH1, and TP53). Overall, pathogenic variants were identified in 5.5% of patients with pancreatic cancer.

Observational studies have reported that pathogenic variants are found in patients with pancreatic cancer who do not have a family history of the disease. In Hu et al pancreatic cancer associated variants were found in 7.9% of patients with a family history of pancreatic cancer and 5.2% of those without a family history of pancreatic cancer (Hu, 2018). Shindo et al reported that pathogenic variants were identified in 3.9% of a cohort of 854 patients with pancreatic adenocarcinoma (Shindo, 2017). Of those with an identified pathogenic variant, only 3 (9.0%) reported a family history of pancreatic cancer.

There are currently no targeted treatments for pancreatic cancer based on germline testing for ATM, CDK2NA, EPCAM, MLH1, MSH2, MSH6, PMS2, STK11, or TP53. It is unclear what management changes would be implemented based on results of such testing.

Genetic Testing in Asymptomatic Individuals who are at Risk for Hereditary Pancreatic Cancer

Multiple genetic syndromes, including hereditary breast and ovarian cancer syndrome, are associated with an increased risk for pancreatic cancer. Most of these are also associated with increased risk of other cancers. However, individual genes associated with the syndromes have been identified as increasing risk of pancreatic cancer, even in the absence of one of these syndromes.

A prospective observational study of individuals under surveillance for pancreatic cancer based on a family history of pancreatic cancer identified a known pathogenic variant in a pancreatic cancer susceptibility gene in 4.3% (15/345) (Abe, 2019). In addition, 66 variants of unclear significance were identified. The cumulative incidence of pancreatic cancer in the germline mutation group was higher than in the familial risk group, adjusted for age and sex and accounting for death as a competing event (HR, 2.85; 95% CI, 1.0 to 8.18; P =.05).

Surveillance in Asymptomatic Individuals at High Risk for Hereditary Pancreatic Cancer

Recent prospective observational studies have reported the yield of screening and outcomes in high-risk individuals enrolled in pancreatic cancer surveillance programs. Surveillance protocols varied somewhat and evolved over time, but typically included annual MRI and/or endoscopic ultrasound, with more frequent follow-up when a suspicious lesion was identified.

A 16-year follow-up study of surveillance in individuals at high-risk of pancreatic cancer due to family history or genetic factors was reported by Canto et al (Canto, 2018). The overall detection rate over 16 years was 7%, including incident and prevalent neoplasms. Of 354 individuals under surveillance, 10 pancreatic cancers were detected, and 9 of 10 were resectable. Among these, 85% survived for 3 years.

Vasen et al found that surveillance of CDNK2A mutation carriers detected most pancreatic adenocarcinomas at a resectable stage (Vasen, 2016). In patients at risk for familial pancreatic cancer (those from families with 2 or 3 ﬁrst-degree relatives with pancreatic cancer), however, the yield of screening was low.

Konings et al published a report of outcomes on 76 high-risk individuals from CAPS surveillance programs in 4 countries (U.S., the Netherlands, Israel, and Italy) who had either undergone pancreatic surgery because of the detection of a suspicious pancreatic lesion (n=71) or progressed to advanced unresectable malignant disease (n=5) (Konings, 2019). Survival rate was significantly poorer for individuals with advanced pancreatic cancer compared with those who had surgery (40% vs. 83% respectively, P =0.050; mean survival 9.5 vs. 54.3 months, P <0.001).

Although observational studies have demonstrated that surveillance can identify pancreatic cancer and precursor lesions in asymptomatic individuals, it is not possible to conclude from this body of evidence that surveillance improves survival. Longer survival time observed in individuals undergoing surveillance could simply be due to earlier identification of the disease (lead-time bias) and not the effects of early intervention and treatment.

Practice Guidelines and Position Statements

American College of Gastroenterology

In 2015, the American College of Gastroenterology Clinical Guideline on Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes includes the following recommendations on genetic testing for pancreatic cancer (Syngal, 2015):

Individuals should be considered to be at risk for familial pancreatic adenocarcinoma if they (i) have a known genetic syndrome associated with pancreatic cancer, including hereditary breast-ovarian cancer syndrome, familial atypical multiple melanoma, and mole syndrome, PJS, LS, or other gene mutations associated with an increased risk of pancreatic adenocarcinoma; or (ii) have 2 relatives with pancreatic adenocarcinoma, where 1 is a first-degree relative; (iii) have 3 or more relatives with pancreatic cancer; or (iv) have a history of hereditary pancreatitis.

Genetic testing of patients with suspected familial pancreatic cancer should include analysis of BRCA1/2, CDKN2A, PALB2, and ATM. Evaluation for PJS, LS, and hereditary pancreatitis-associated genes should be considered if other component personal and/or family history criteria are met for the syndrome.

American Society of Clinical Oncology

In 2019, an American Society of Clinical Oncology (ASCO) opinion statement addressed the identification and management of patients and family members with a possible predisposition to pancreatic adenocarcinoma and made the following recommendations (Stoffel, 2019):

PCO 1.2 Individuals with a family history of pancreatic cancer affecting 2 first-degree relatives meet the criteria for familial pancreatic cancer. Individuals whose family history meets criteria for familial pancreatic cancer, those with 3e or more diagnoses of pancreatic cancer in the same side of the family, and individuals meeting criteria for other genetic syndromes associated with increased risk for pancreatic cancer have an increased risk for pancreatic cancer and are candidates for genetic testing (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

PCO 1.3 Genetic risk evaluation should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer syndromes to determine the most appropriate testing strategy and discuss implications of the findings for family members. Germline genetic testing for patients with pancreatic cancer should be offered in the context of shared decision making. (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

PCO 2.1 All patients diagnosed with pancreatic adenocarcinoma should undergo an assessment of risk for hereditary syndromes known to be associated with an increased risk for pancreatic adenocarcinoma. Assessment of risk includes obtaining a personal cancer history and family history of cancers in first- and second-degree relatives. However, recent data demonstrate that many individuals who develop pancreatic cancer in the setting of genetic predisposition lack clinical features or family cancer history typically associated with the corresponding hereditary syndrome. Therefore, germline genetic testing may be discussed with patients with a personal history of pancreatic cancer, even if family history is unremarkable (Type: informal consensus; benefits outweigh harms; Strength of statement: strong).

In 2020, ASCO published a guideline update on recommendations for second-line therapy options for metastatic pancreatic cancer (Sohal, 2020). In patients who have a germline BRCA1 or BRCA2 mutation and who have received first-line platinum-based chemotherapy without disease progression for at least 16 weeks, options for continued treatment include chemotherapy or the PARP inhibitor olaparib.

International Cancer of the Pancreas Screening Consortium

In 2020, the International Cancer of the Pancreas Screening Consortium published an updated consensus document on the management of patients with increased risk for familial pancreatic cancer (Goggins, 2020). The panel recommended pancreatic cancer surveillance performed in a research setting for the following individuals:

All patients with Peutz-Jeghers syndrome (carriers of a germline LKB1/STK11 gene mutation)

All carriers of a germline CDKN2A mutation

Carriers of a germline BRCA2, BRCA1, PALB2, ATM, MLH1, MSH2, or MSH6 gene mutation with at least 1 affected first-degree blood relative

Individuals who have at least 1 first-degree relative with pancreatic cancer who in turn also has a first-degree relative with pancreatic cancer (familial pancreatic cancer kindred)

The preferred surveillance tests are endoscopic ultrasound and magnetic resonance imaging (MRI). The recommended age to initiate surveillance depends on an individual's gene mutation status and family history, but no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer. There was no consensus on the age to end surveillance.

National Comprehensive Cancer Network

Two National Comprehensive Cancer Network (NCCN) guidelines address germline genetic testing in individuals with or at high risk for pancreatic cancer (NCCN, 2021).

The Guidelines on Genetic/Familial High-risk Assessment: Breast, Ovarian, and Pancreatic (v.2.2021) recommend germline testing for all individuals with exocrine pancreatic cancer, and specify that testing of first-degree relatives should only be done only if it is impossible to test the individual who has pancreatic cancer (NCCN, 2021).

The Guideline on Treatment of Pancreatic Adenocarcinoma (v.1.2021) recommends germline testing for any patient with confirmed pancreatic cancer using comprehensive gene panels for hereditary cancer syndromes (NCCN, 2021). The guideline specifies the following genes as those typically tested for pancreatic cancer risk: ATM, BRCA1, BRCA2, CDKN2A, most Lynch syndrome genes (MLH1, MSH2, MSH6, EPCAM), PALB2, STK11, and TP53. For patients with locally advanced disease, preferred first-line therapy regimens include gemcitabine + cisplatin for patients with BRCA1/2 or PALB2 variants For patients with metastatic disease who have received previous platinum-based chemotherapy, olaparib is preferred only for patients with germline BRCA 1/2 variants.

Genetic counseling is recommended for patients who test positive for a pathogenic variant, or for patients with a positive family history of pancreatic cancer, regardless of test results. The guidelines also recommend genetic counseling for patients who test positive for a pathogenic variant or for patients with a positive family history of pancreatic cancer, regardless of variant status.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed below.

Ongoing

NCT03140670 A Phase 2, Open Label Study of Rucaparib in Patients With Advanced Pancreatic Cancer and a Known Deleterious Germline or Somatic BRCA or PALB2 Mutation (Completion Date: Jun 2022)

NCT02790944a Utilizing a Multi-gene Testing Approach to Identify Hereditary Pancreatic Cancer in Consecutive Cases Unselected for Family History (Completion Date: May 2021)

NCT03060720 Systematic Hereditary Pancreatic Cancer Risk Assessment and Implications for Personalized Therapy (Completion Date: Feb 2022)

NCT00835133 Biospecimen Resource for Familial Pancreas Research, a Data and Tissue Registry (Also Known as a Bio-repository, Bio-bank, Data and Tissue Database, Data and Tissue Bank, Etc.) to Help Advance Research in Familial Pancreas Disease (Completion Date: Sep 2022)

NCT02206360 Observational Study to Analyze the Outcomes of Subjects Who - Based Upon Their Sufficiently Elevated Risk for the Development of Pancreatic Adenocarcinoma- Elect to Undergo Early Detection Testing (Completion Date: Mar 2024)

NCT00526578 Pancreatic Cancer Genetic Epidemiology (PACGENE) Study (Completion Date: Jun 2025)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Dbouk et al published results of the CAPS5 cohort, consisting of 1461 individuals who were determined to be at high risk for PDAC based either on presence of a germline pathogenic variant (48.5%) or family history without a known germline pathogenic variant (51.5%) (Dbouk, 2022). A total of 9 individuals were diagnosed with a screen-detected pancreatic adenocarcinoma. The study authors concluded that their results "support current CAPS surveillance recommendations and argue against the notion of limiting pancreatic surveillance to those high-risk individuals with known pathogenic mutations."

In a cohort of 366 Dutch individuals at high risk of PDAC followed for 63 months (standard deviation, 43.2 months), Overbeek et al reported a 9.3% incidence of PDAC in the subset of individuals with a germline pathogenic variant and no PDAC in those with family history but no pathogenic variant (Overbeek, 2022). Three out of 10 (30%) individuals with PDAC were detected at an early stage. The resectability rate was 60% (6/10) overall and 50% (4/8) for incident cases.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

0129U	Hereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer), genomic sequence analysis and deletion/duplication analysis panel (ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, and TP53)
81162	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (ie, detection of large gene rearrangements)
81163	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81164	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81165	BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81166	BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81167	BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)
81201	APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence
81212	BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; 185delAG, 5385insC, 6174delT variants
81215	BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant
81216	BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis
81217	BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant
81288	MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis
81292	MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81293	MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81294	MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81295	MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81298	MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81299	MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81300	MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81307	PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; full gene sequence
81308	PALB2 (partner and localizer of BRCA2) (eg, breast and pancreatic cancer) gene analysis; known familial variant
81317	PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis
81318	PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81319	PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81403	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) ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence ARX (aristaless-related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), duplication/deletion analysis CEL (carboxyl ester lipase [bile salt-stimulated lipase]) (eg, maturity-onset diabetes of the young [MODY]), targeted sequence analysis of exon 11 (eg, c.1785delC, c.1686delT) CTNNB1 (catenin [cadherin-associated protein], beta 1, 88kDa) (eg, desmoid tumors), targeted sequence analysis (eg, exon 3) DAZ/SRY (deleted in azoospermia and sex determining region Y) (eg, male infertility), common deletions (eg, AZFa, AZFb, AZFc, AZFd) DNMT3A (DNA [cytosine-5-]-methyltransferase 3 alpha) (eg, acute myeloid leukemia), targeted sequence analysis (eg, exon 23) EPCAM (epithelial cell adhesion molecule) (eg, Lynch syndrome), duplication/deletion analysis F8 (coagulation factor VIII) (eg, hemophilia A), inversion analysis, intron 1 and intron 22A F12 (coagulation factor XII [Hageman factor]) (eg, angioedema, hereditary, type III; factor XII deficiency), targeted sequence analysis of exon 9 FGFR3 (fibroblast growth factor receptor 3) (eg, isolated craniosynostosis), targeted sequence analysis (eg, exon 7) (For targeted sequence analysis of multiple FGFR3 exons, use 81404) GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full gene sequence GNAQ (guanine nucleotide-binding protein G[q] subunit alpha) (eg, uveal melanoma), common variants (eg, R183, Q209) Human erythrocyte antigen gene analyses (eg, SLC14A1 [Kidd blood group], BCAM [Lutheran blood group], ICAM4 [Landsteiner-Wiener blood group], SLC4A1 [Diego blood group], AQP1 [Colton blood group], ERMAP [Scianna blood group], RHCE [Rh blood group, CcEe antigens], KEL [Kell blood group], DARC [Duffy blood group], GYPA, GYPB, GYPE [MNS blood group], ART4 [Dombrock blood group]) (eg, sickle-cell disease, thalassemia, hemolytic transfusion reactions, hemolytic disease of the fetus or newborn), common variants HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), exon 2 sequence KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2) KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2) (eg, Andersen-Tawil syndrome), full gene sequence KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) (eg, familial hyperinsulinism), full gene sequence Killer cell immunoglobulin-like receptor (KIR) gene family (eg, hematopoietic stem cell transplantation), genotyping of KIR family genes 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) MC4R (melanocortin 4 receptor) (eg, obesity), full gene sequence MICA (MHC class I polypeptide-related sequence A) (eg, solid organ transplantation), common variants (eg, 001, 002) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), full gene sequence MT-TS1 (mitochondrially encoded tRNA serine 1) (eg, nonsyndromic hearing loss), full gene sequence NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), duplication/deletion analysis NHLRC1 (NHL repeat containing 1) (eg, progressive myoclonus epilepsy), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), duplication/deletion analysis PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene) RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene), performed on cell-free fetal DNA in maternal blood (For human erythrocyte gene analysis of RHD, use a separate unit of 81403) SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), duplication/deletion analysis TWIST1 (twist homolog 1 [Drosophila]) (eg, Saethre-Chotzen syndrome), duplication/deletion analysis UBA1 (ubiquitin-like modifier activating enzyme 1) (eg, spinal muscular atrophy, X-linked), targeted sequence analysis (eg, exon 15) VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), deletion/duplication analysis VWF (von Willebrand factor) (eg, von Willebrand disease types 2A, 2B, 2M), targeted sequence analysis (eg, exon 28)
81404	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) ACADS (acyl-CoA dehydrogenase, C-2 to C-3 short chain) (eg, short chain acyl-CoA dehydrogenase deficiency), targeted sequence analysis (eg, exons 5 and 6) AQP2 (aquaporin 2 [collecting duct]) (eg, nephrogenic diabetes insipidus), full gene sequence ARX (aristaless related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), full gene sequence AVPR2 (arginine vasopressin receptor 2) (eg, nephrogenic diabetes insipidus), full gene sequence BBS10 (Bardet-Biedl syndrome 10) (eg, Bardet-Biedl syndrome), full gene sequence BTD (biotinidase) (eg, biotinidase deficiency), full gene sequence C10orf2 (chromosome 10 open reading frame 2) (eg, mitochondrial DNA depletion syndrome), full gene sequence CAV3 (caveolin 3) (eg, CAV3-related distal myopathy, limb-girdle muscular dystrophy type 1C), full gene sequence CD40LG (CD40 ligand) (eg, X-linked hyper IgM syndrome), full gene sequence CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence CLRN1 (clarin 1) (eg, Usher syndrome, type 3), full gene sequence COX6B1 (cytochrome c oxidase subunit VIb polypeptide 1) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence CPT2 (carnitine palmitoyltransferase 2) (eg, carnitine palmitoyltransferase II deficiency), full gene sequence CRX (cone-rod homeobox) (eg, cone-rod dystrophy 2, Leber congenital amaurosis), full gene sequence CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (eg, primary congenital glaucoma), full gene sequence EGR2 (early growth response 2) (eg, Charcot-Marie-Tooth), full gene sequence EMD (emerin) (eg, Emery-Dreifuss muscular dystrophy), duplication/deletion analysis EPM2A (epilepsy, progressive myoclonus type 2A, Lafora disease [laforin]) (eg, progressive myoclonus epilepsy), full gene sequence FGF23 (fibroblast growth factor 23) (eg, hypophosphatemic rickets), full gene sequence FGFR2 (fibroblast growth factor receptor 2) (eg, craniosynostosis, Apert syndrome, Crouzon syndrome), targeted sequence analysis (eg, exons 8, 10) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), targeted sequence analysis (eg, exons 8, 11, 12, 13) FHL1 (four and a half LIM domains 1) (eg, Emery-Dreifuss muscular dystrophy), full gene sequence FKRP (fukutin related protein) (eg, congenital muscular dystrophy type 1C [MDC1C], limb-girdle muscular dystrophy [LGMD] type 2I), full gene sequence FOXG1 (forkhead box G1) (eg, Rett syndrome), full gene sequence FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), evaluation to detect abnormal (eg, deleted) alleles FSHMD1A (facioscapulohumeral muscular dystrophy 1A) (eg, facioscapulohumeral muscular dystrophy), characterization of haplotype(s) (ie, chromosome 4A and 4B haplotypes) GH1 (growth hormone 1) (eg, growth hormone deficiency), full gene sequence GP1BB (glycoprotein Ib [platelet], beta polypeptide) (eg, Bernard-Soulier syndrome type B), full gene sequence (For common deletion variants of alpha globin 1 and alpha globin 2 genes, use 81257) HNF1B (HNF1 homeobox B) (eg, maturity-onset diabetes of the young [MODY]), duplication/deletion analysis HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), full gene sequence HSD3B2 (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) (eg, 3-beta-hydroxysteroid dehydrogenase type II deficiency), full gene sequence HSD11B2 (hydroxysteroid [11-beta] dehydrogenase 2) (eg, mineralocorticoid excess syndrome), full gene sequence HSPB1 (heat shock 27kDa protein 1) (eg, Charcot-Marie-Tooth disease), full gene sequence INS (insulin) (eg, diabetes mellitus), full gene sequence KCNJ1 (potassium inwardly-rectifying channel, subfamily J, member 1) (eg, Bartter syndrome), full gene sequence KCNJ10 (potassium inwardly-rectifying channel, subfamily J, member 10) (eg, SeSAME syndrome, EAST syndrome, sensorineural hearing loss), full gene sequence LITAF (lipopolysaccharide-induced TNF factor) (eg, Charcot-Marie-Tooth), full gene sequence MEFV (Mediterranean fever) (eg, familial Mediterranean fever), full gene sequence MEN1 (multiple endocrine neoplasia I) (eg, multiple endocrine neoplasia type 1, Wermer syndrome), duplication/deletion analysis MMACHC (methylmalonic aciduria [cobalamin deficiency] cblC type, with homocystinuria) (eg, methylmalonic acidemia and homocystinuria), full gene sequence MPV17 (MpV17 mitochondrial inner membrane protein) (eg, mitochondrial DNA depletion syndrome), duplication/deletion analysis NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), full gene sequence NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 1, 7.5kDa) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFAF2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, assembly factor 2) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NDUFS4 (NADH dehydrogenase [ubiquinone] Fe-S protein 4, 18kDa [NADH-coenzyme Q reductase]) (eg, Leigh syndrome, mitochondrial complex I deficiency), full gene sequence NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) (eg, spastic paraplegia), full gene sequence NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis NPC2 (Niemann-Pick disease, type C2 [epididymal secretory protein E1]) (eg, Niemann-Pick disease type C2), full gene sequence NR0B1 (nuclear receptor subfamily 0, group B, member 1) (eg, congenital adrenal hypoplasia), full gene sequence PDX1 (pancreatic and duodenal homeobox 1) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), full gene sequence PLP1 (proteolipid protein 1) (eg, Pelizaeus-Merzbacher disease, spastic paraplegia), duplication/deletion analysis PQBP1 (polyglutamine binding protein 1) (eg, Renpenning syndrome), duplication/deletion analysis PRNP (prion protein) (eg, genetic prion disease), full gene sequence PROP1 (PROP paired-like homeobox 1) (eg, combined pituitary hormone deficiency), full gene sequence PRPH2 (peripherin 2 [retinal degeneration, slow]) (eg, retinitis pigmentosa), full gene sequence PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1) (eg, LEOPARD syndrome), targeted sequence analysis (eg, exons 7, 12, 14, 17) RET (ret proto-oncogene) (eg, multiple endocrine neoplasia, type 2B and familial medullary thyroid carcinoma), common variants (eg, M918T, 2647_2648delinsTT, A883F) RHO (rhodopsin) (eg, retinitis pigmentosa), full gene sequence RP1 (retinitis pigmentosa 1) (eg, retinitis pigmentosa), full gene sequence SCN1B (sodium channel, voltage-gated, type I, beta) (eg, Brugada syndrome), full gene sequence SCO2 (SCO cytochrome oxidase deficient homolog 2 [SCO1L]) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence SDHC (succinate dehydrogenase complex, subunit C, integral membrane protein, 15kDa) (eg, hereditary paraganglioma-pheochromocytoma syndrome), duplication/deletion analysis SDHD (succinate dehydrogenase complex, subunit D, integral membrane protein) (eg, hereditary paraganglioma), full gene sequence SGCG (sarcoglycan, gamma [35kDa dystrophin-associated glycoprotein]) (eg, limb-girdle muscular dystrophy), duplication/deletion analysis SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), full gene sequence SLC16A2 (solute carrier family 16, member 2 [thyroid hormone transporter]) (eg, specific thyroid hormone
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) 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 (When performing cytogenomic [genome-wide] analysis, for constitutional chromosomal abnormalities. See 81228, 81229, 81349)
81406	Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons) ACADVL (acyl-CoA dehydrogenase, very long chain) (eg, very long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence ACTN4 (actinin, alpha 4) (eg, focal segmental glomerulosclerosis), full gene sequence AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence AIRE (autoimmune regulator) (eg, autoimmune polyendocrinopathy syndrome type 1), full gene sequence ALDH7A1 (aldehyde dehydrogenase 7 family, member A1) (eg, pyridoxine-dependent epilepsy), full gene sequence ANO5 (anoctamin 5) (eg, limb-girdle muscular dystrophy), full gene sequence ANOS1 (anosmin-1) (eg, Kallmann syndrome 1), full gene sequence APP (amyloid beta [A4] precursor protein) (eg, Alzheimer disease), full gene sequence ASS1 (argininosuccinate synthase 1) (eg, citrullinemia type I), full gene sequence ATL1 (atlastin GTPase 1) (eg, spastic paraplegia), full gene sequence ATP1A2 (ATPase, Na+/K+ transporting, alpha 2 polypeptide) (eg, familial hemiplegic migraine), full gene sequence ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence BBS1 (Bardet-Biedl syndrome 1) (eg, Bardet-Biedl syndrome), full gene sequence BBS2 (Bardet-Biedl syndrome 2) (eg, Bardet-Biedl syndrome), full gene sequence BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence BEST1 (bestrophin 1) (eg, vitelliform macular dystrophy), full gene sequence BMPR2 (bone morphogenetic protein receptor, type II [serine/threonine kinase]) (eg, heritable pulmonary arterial hypertension), full gene sequence BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, Noonan syndrome), full gene sequence BSCL2 (Berardinelli-Seip congenital lipodystrophy 2 [seipin]) (eg, Berardinelli-Seip congenital lipodystrophy), full gene sequence BTK (Bruton agammaglobulinemia tyrosine kinase) (eg, X-linked agammaglobulinemia), full gene sequence CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) (eg, Brugada syndrome), full gene sequence CAPN3 (calpain 3) (eg, limb-girdle muscular dystrophy [LGMD] type 2A, calpainopathy), full gene sequence CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), full gene sequence CDH1 (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer), full gene sequence CDKL5 (cyclin-dependent kinase-like 5) (eg, early infantile epileptic encephalopathy), full gene sequence CLCN1 (chloride channel 1, skeletal muscle) (eg, myotonia congenita), full gene sequence CLCNKB (chloride channel, voltage-sensitive Kb) (eg, Bartter syndrome 3 and 4b), full gene sequence CNTNAP2 (contactin-associated protein-like 2) (eg, Pitt-Hopkins-like syndrome 1), full gene sequence COL6A2 (collagen, type VI, alpha 2) (eg, collagen type VI-related disorders), duplication/deletion analysis CPT1A (carnitine palmitoyltransferase 1A [liver]) (eg, carnitine palmitoyltransferase 1A [CPT1A] deficiency), full gene sequence CRB1 (crumbs homolog 1 [Drosophila]) (eg, Leber congenital amaurosis), full gene sequence CREBBP (CREB binding protein) (eg, Rubinstein-Taybi syndrome), duplication/deletion analysis DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence DLAT (dihydrolipoamide S-acetyltransferase) (eg, pyruvate dehydrogenase E2 deficiency), full gene sequence DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence DSC2 (desmocollin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence DSG2 (desmoglein 2) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 10), full gene sequence DSP (desmoplakin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 8), full gene sequence EFHC1 (EF-hand domain [C-terminal] containing 1) (eg, juvenile myoclonic epilepsy), full gene sequence EIF2B3 (eukaryotic translation initiation factor 2B, subunit 3 gamma, 58kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B4 (eukaryotic translation initiation factor 2B, subunit 4 delta, 67kDa) (eg, leukoencephalopathy with vanishing white matter), full gene sequence EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence ENG (endoglin) (eg, hereditary hemorrhagic telangiectasia, type 1), full gene sequence EYA1 (eyes absent homolog 1 [Drosophila]) (eg, branchio-oto-renal [BOR] spectrum disorders), full gene sequence F8 (coagulation factor VIII) (eg, hemophilia A), duplication/deletion analysis FAH (fumarylacetoacetate hydrolase [fumarylacetoacetase]) (eg, tyrosinemia, type 1), full gene sequence FASTKD2 (FAST kinase domains 2) (eg, mitochondrial respiratory chain complex IV deficiency), full gene sequence FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing [S. cerevisiae]) (eg, Charcot-Marie-Tooth disease), full gene sequence FTSJ1 (FtsJ RNA methyltransferase homolog 1 [E. coli]) (eg, X-linked mental retardation 9), full gene sequence FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence GARS (glycyl-tRNA synthetase) (eg, Charcot-Marie-Tooth disease), full gene sequence GCDH (glutaryl-CoA dehydrogenase) (eg, glutaricacidemia type 1), full gene sequence GCK (glucokinase [hexokinase 4]) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence GLUD1 (glutamate dehydrogenase 1) (eg, familial hyperinsulinism), full gene sequence GNE (glucosamine [UDP-N-acetyl]-2-epimerase/N-acetylmannosamine kinase) (eg, inclusion body myopathy 2 [IBM2], Nonaka myopathy), full gene sequence GRN (granulin) (eg, frontotemporal dementia), full gene sequence HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein] alpha subunit) (eg, long chain acyl-coenzyme A dehydrogenase deficiency), full gene sequence HADHB (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase [trifunctional protein], beta subunit) (eg, trifunctional protein deficiency), full gene sequence HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence HLCS (HLCS holocarboxylase synthetase) (eg, holocarboxylase synthetase deficiency), full gene sequence HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence HNF4A (hepatocyte nuclear factor 4, alpha) (eg, maturity-onset diabetes of the young [MODY]), full gene sequence IDUA (iduronidase, alpha-L-) (eg, mucopolysaccharidosis type I), full gene sequence INF2 (inverted formin, FH2 and WH2 domain containing) (eg, focal segmental glomerulosclerosis), full gene sequence IVD (isovaleryl-CoA dehydrogenase) (eg, isovaleric acidemia), full gene sequence JAG1 (jagged 1) (eg, Alagille syndrome), duplication/deletion analysis JUP (junction plakoglobin) (eg, arrhythmogenic right ventricular dysplasia/cardiomyopathy 11), full gene sequence KCNH2 (potassium voltage-gated channel, subfamily H [eag-related], member 2) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) (eg, short QT syndrome, long QT syndrome), full gene sequence KCNQ2 (potassium voltage-gated channel, KQT-like subfamily, member 2) (eg, epileptic encephalopathy), full gene sequence LDB3 (LIM domain binding 3) (eg, familial dilated cardiomyopathy, myofibrillar myopathy), full gene sequence LDLR (low den
81432	Hereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53
81433	Hereditary breast cancer related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); duplication/deletion analysis panel, must include analyses for BRCA1, BRCA2, MLH1, MSH2, and STK11
81435	Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11
81436	Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAD4, and STK11
81445	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; DNA analysis or combined DNA and RNA analysis
81449	Targeted genomic sequence analysis panel, solid organ neoplasm, 5-50 genes RNA analysis
81455	Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, 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; DNA analysis or combined DNA and RNA analysis
81456	Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes RNA analysis

References:

Abe T, Blackford AL, Tamura K, et al.(2019) Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. J Clin Oncol. May 01 2019; 37(13): 1070-1080. PMID 30883245

Brand R, Borazanci E, Speare V, et al.(2018) Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. Cancer. Sep 01 2018; 124(17): 3520-3527. PMID 30067863

Canto MI, Almario JA, Schulick RD, et al.(2018) Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance. Gastroenterology. Sep 2018; 155(3): 740-751.e2. PMID 29803839

Dbouk M, Katona BW, Brand RE, et al.(2022) The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival. J Clin Oncol. Oct 01 2022; 40(28): 3257-3266. PMID 35704792

Food & Drug Administration.(2021) Premarket Approval: BRACAnalysis CDx. 2019. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140020S019. Accessed January 18, 2021.

Goggins M, Overbeek KA, Brand R, et al.(2020) Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. Jan 2020; 69(1): 7-17. PMID 31672839

Golan T, Hammel P, Reni M, et al.(2019) Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer. N Engl J Med. Jul 25 2019; 381(4): 317-327. PMID 31157963

Golan T, Kanji ZS, Epelbaum R, et al.(2014) Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. Sep 09 2014; 111(6): 1132-8. PMID 25072261

Grant RC, Selander I, Connor AA, et al.(2018) Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology. Mar 2015; 148(3): 556-64. PMID 25479140

Hu C, Hart SN, Polley EC, et al.(2018) Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. Jun 19 2018; 319(23): 2401-2409. PMID 29922827

Konings ICAW, Canto MI, Almario JA, et al.(2019) Surveillance for pancreatic cancer in high-risk individuals. BJS Open. Oct 2019; 3(5): 656-665. PMID 31592073

Mandelker D, Zhang L, Kemel Y, et al.(2017) Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. Sep 05 2017; 318(9): 825-835. PMID 28873162

National Comprehensive Cancer Network (NCCN).(2021) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed January 16, 2021.

National Comprehensive Cancer Network (NCCN).(2021) Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 1.2021. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed January 15, 2021.

NIH National Cancer Institute: Surveillance, Epidemiology, and End Results Program.(2021) Cancer Stat Facts: Pancreatic Cancer. 2019. https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed January 15, 2021.

O'Reilly EM, Lee JW, Zalupski M, et al.(2020) Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. May 01 2020; 38(13): 1378-1388. PMID 31976786

Overbeek KA, Levink IJM, Koopmann BDM, et al.(2022) Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut. Jun 2022; 71(6): 1152-1160. PMID 33820756

Owens DK, Davidson KW, Krist AH, et al.(2019) Screening for Pancreatic Cancer: US Preventive Services Task Force Reaffirmation Recommendation Statement. JAMA. Aug 06 2019; 322(5): 438-444. PMID 31386141

Reiss KA, Yu S, Judy R, et al.(2018) Retrospective Survival Analysis of Patients With Advanced Pancreatic Ductal Adenocarcinoma and Germline BRCA or PALB2 Mutations. JCO Precision Oncology. Published online January 19, 2018. DOI: 10.1200/PO.17.00152.

Shindo K, Yu J, Suenaga M, et al.(2017) Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. J Clin Oncol. Oct 20 2017; 35(30): 3382-3390. PMID 28767289

Sohal DPS, Kennedy EB, Cinar P, et al.(2020) Metastatic Pancreatic Cancer: ASCO Guideline Update. J Clin Oncol. Aug 05 2020: JCO2001364. PMID 32755482

Stoffel EM, McKernin SE, Khorana AA.(2019) Evaluating Susceptibility to Pancreatic Cancer: ASCO Clinical Practice Provisional Clinical Opinion Summary. J Oncol Pract. Feb 2019; 15(2): 108-111. PMID 30589608

Syngal S, Brand RE, Church JM, et al.(2015) ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. Feb 2015; 110(2): 223-62; quiz 263. PMID 25645574

Vasen H, Ibrahim I, Ponce CG, et al.(2016) Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers. J Clin Oncol. Jun 10 2016; 34(17): 2010-9. PMID 27114589

Wattenberg MM, Asch D, Yu S, et al.(2020) Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation. Br J Cancer. Feb 2020; 122(3): 333-339. PMID 31787751

Yu S, Agarwal P, Mamtani R, et al.(2019) Retrospective survival analysis of patients with resected pancreatic ductal adenocarcinoma and a Germline BRCA or PALB2 mutation. JCO Precision Oncol. Published online March 28, 2019. DOI: 10.1200/PO.18.00271

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.