MEDICAL POLICY 12.04.99

Genetic Testing for Hereditary Pancreatitis

BCBSA Ref. Policy: 2.04.99

Effective Date: May 1, 2018

Last Revised: April 3, 2018

Replaces: 2.04.99

RELATED MEDICAL POLICIES:

None

Select a hyperlink below to be directed to that section.

POLICY CRITERIA | CODING | RELATED INFORMATION

EVIDENCE REVIEW | REFERENCES | HISTORY

Clicking this icon returns you to the hyperlinks menu above.

Introduction

The pancreas is an important organ behind and below the stomach. It releases enzymes to help

us digest our food and also releases hormones (insulin and glucagon) to help the body control

how it uses the food for energy. If the pancreas becomes inflamed, it is called pancreatitis. In

some people, pancreatitis may have come on suddenly and only lasts for a short time (acute

pancreatitis). Other people may have been sick with pancreatitis for a long time (chronic

pancreatitis). Chronic pancreatitis may seem to run in some families, and as a result these cases

may be caused by genetic problems. Genetic testing has sometimes been done to see if a

person has hereditary pancreatitis. This policy discusses when genetic testing for hereditary

pancreatitis may be medically necessary.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The

rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for

providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can

be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a

service may be covered.

Policy Coverage Criteria

Page | 2 of 12

Testing Medical Necessity Genetic testing for

hereditary pancreatitis

Genetic testing for hereditary pancreatitis may be considered

medically necessary for patients aged 18 years and younger

with unexplained recurrent (greater than 1 episode) acute or

chronic pancreatitis with documented elevated amylase or

lipase levels.

Testing Investigational Genetic testing for

hereditary pancreatitis

Genetic testing for hereditary pancreatitis is considered

investigational in all other situations.

Coding

Code Description

CPT 81223 CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene

analysis; full gene sequence

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)

Includes the following tests:

PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants

(eg, N29I, A16V,R122H)

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)

Includes the following tests:

PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), full gene sequence,

SPINK1 (serine peptidase inhibitor, Kazal type 1) (eg, hereditary pancreatitis), full gene

sequence

81479 Unlisted molecular pathology

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS

codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

Page | 3 of 12

Related Information

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and

experts recommend formal genetic counseling in most cases when genetic testing for an

inherited condition is considered. The interpretation of the results of genetic tests and the

understanding of risk factors can be very difficult and complex. Therefore, genetic counseling

will assist individuals in understanding the possible benefits and harms of genetic testing,

including the possible impact of the information on the individuals family. Genetic counseling

may alter the utilization of genetic testing substantially and may reduce inappropriate testing.

Genetic counseling should be performed by an individual with experience and expertise in

genetic medicine and genetic testing methods.

Consideration of Age

The age described in this policy for medical necessity of genetic testing for hereditary

pancreatitis is age 18 and younger. Having recurrent pancreatitis in children is not very

common. The literature regarding genetic testing for hereditary pancreatitis in children is sparse.

Although there is a lot of evidence, there is consensus opinion from physician medical societies

that, in children with more than one episode of pancreatitis, a positive result of this genetic

testing may make additional invasive testing unnecessary. See the Evidence Review section

below for more detail.

Evidence Review

Description

In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic

inflammatory state with exocrine insufficiency, diabetes mellitus, and increased risk for

pancreatic cancer. Hereditary pancreatitis (HP) is a subset of CP defined clinically as a familial

pattern of CP. Variants of several genes are associated with HP. Demonstration of a pathogenic

genetic variant in one or several of these genes can potentially be used to confirm the diagnosis

Page | 4 of 12

of HP, provide information on prognosis and management, and/or determine the risk of CP in

asymptomatic relatives of patients with HP.

Background

Pancreatitis

Acute and chronic pancreatitis (CP) is caused by the premature activation of trypsinogen into

trypsin within the pancreas, resulting in autodigestion, inflammation, increased levels of

pancreatic enzymes in the serum, and abdominal pain. CP is defined as an ongoing

inflammatory state associated with chronic/recurrent symptoms and progression to exocrine

and endocrine pancreatic insufficiency.

Alcohol is the major etiologic factor in 80% of CP, which has a peak incidence in the fourth and

fifth decades of life. Gall stones, hypercalcemia, inflammatory bowel disease, autoimmune

pancreatitis, and peptic ulcer disease can also cause CP. About 20% of CP is idiopathic.

A small percentage of CP is categorized as hereditary pancreatitis (HP), which usually begins

with recurrent episodes of acute pancreatitis in childhood and evolves into CP by age 20 years.

Multiple family members may be affected over several generations, and pedigree analysis often

reveals an autosomal dominant pattern of inheritance. Clinical presentation and family history

alone are sometimes insufficient to distinguish between idiopathic CP and HP, especially early in

the course of the disease. Individuals with HP have an estimated 40% to 55% lifetime risk of

developing pancreatic cancer.1

Genetic Determinants of Hereditary Pancreatitis (HP)

PRSS1 Variant

Whitcomb (2001) discovered that disease-associated variants of protease, serine, 1 (trypsin 1)

(PRSS1) on chromosome 7q35 cause HP. PRSS1 encodes cationic trypsinogen. The gain of

function variants of the PRSS1 gene cause HP by prematurely and excessively converting

trypsinogen to trypsin, which results in pancreatic autodigestion. Between 60% and 80% of

people who have a disease-associated PRSS1 variant will experience pancreatitis in their

lifetimes; 30% to 40% will develop CP. Most, but not all, people with a disease-associated variant

of PRSS1 will have inherited it from one of their parents. The proportion of HP caused by a de

novo variant of PRSS1 is unknown. In families with 2 or more affected individuals in 2 or more

Page | 5 of 12

generations, genetic testing has shown that most have a demonstrable disease-associated

PRSS1 variant. In 60% to 100%, the variant is detected by sequencing technology (Sanger or

next-generation), and duplications of exons or the whole PRSS1 gene are seen in about 6%. Two

PRSS1 point variants (p.Arg122His, p.Asn29Ile) are most common, accounting for 90% of

disease-associated variants in affected individuals. Over 40 other PRSS1 sequence variants have

been found, but their clinical significance is uncertain. Pathogenic PRSS1 variants are present in

10% or less of individuals with CP.2

Targeted analysis of exons 2 and 3, where the common disease-associated variants are found, or

PRSS1 sequencing, are first-line tests, followed by duplication analysis. The general indications

for PRSS1 testing and emphasis on pre- and post-test genetic counseling have remained central

features of reviews and guidelines.3,4 However, several other genes have emerged as significant

contributors to both HP and CP. They include the cystic fibrosis (CF) transmembrane

conductance regulator (CFTR) gene, serine peptidase inhibitor, Kazal type 1 (SPINK1) gene,

chymotrypsin C (CTRC) gene, and claudin-2 (CLDN-2) gene.

CFTR Variants

Autosomal recessive variants of CFTR cause CF, a chronic disease with onset in childhood that

causes severe sinopulmonary disease and numerous gastrointestinal abnormalities. The signs

and symptoms of CF can vary widely. On rare occasions, an affected individual may have mild

pulmonary disease, pancreatic exocrine sufficiency, and may present with acute, recurrent acute,

or CP.3 Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold

increased risk for CP. Individuals with 2 CFTR variants (homozygotes or compound

heterozygotes) will benefit from CF-specific evaluations, therapies, and genetic counseling.

SPINK Variants

The SPINK gene encodes a protein that binds to trypsin and thereby inhibits its activity. Variants

in SPINK are not associated with acute pancreatitis but are found, primarily as modifiers, in

recurrent acute pancreatitis and seem to promote the development of CP, including for

individuals with compound heterozygous variants of the CFTR gene. Autosomal recessive

familial pancreatitis may be caused by homozygous or compound heterozygous SPINK variants.5

Page | 6 of 12

CTRC Variants

CTRC is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W and

p.K247_R254del) are associated with an increased risk for idiopathic CP (odds ratio [OR], 4.6),

alcoholic pancreatitis (OR =4.2), and tropical pancreatitis (OR =13.6).6

CLDN2 Variants

CLDN2 encodes a member of the claudin protein family, which acts as an integral membrane

protein at tight junctions and has tissue-specific expression. Several single nucleotide

polymorphisms in CLDN2 have been associated with CP.

Genetic Testing for Variants

Testing for variants associated with HP is typically done by direct sequence analysis or next-

generation sequencing (NGS). A number of laboratories offer testing for the relevant genes,

either individually or as panels. For example, ARUP Laboratories (Salt Lake City, UT) offers a

Pancreatitis Panel, which includes direct (Sanger) sequencing of CFTR, CTRC, PRSS1, and SPINK.7

Prevention Genetics (Marshfield, WI) offers a Chronic Pancreatitis Sequencing Panel, which

includes NGS of 5 genes: CASR, CFTR, CTRC, PRSS1, and SPINK1.8 Ambry Genetics (Aliso Viejo,

CA) offers a Pancreatitis Panel, which includes NGS of PRSS1, SPINK1, CTRC, and CFTR.9 Ambrys

PancNext panel for variants associated with increased risk of pancreatic cancer consists of NGS

of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A, EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2,

STK11, and TP53.10

Summary of Evidence

For individuals who have CP or ARP who receive testing for genes associated with HP, the

evidence includes cohort studies on variant detection rates and a systematic review. Relevant

outcomes are test accuracy, symptoms, change in disease status, morbid events, and

hospitalizations. There are studies on the detection rate of HP-associated genes in various

populations. Few studies have enrolled patients with known HP; those doing so have reported

detection rates for disease-associated variants between 52% and 62%. For other studies that

tested patients with CP or ARP, disease-associated variant detection rates varied widely across

studies. There is a lack of direct evidence that testing for HP improves health outcomes and

Page | 7 of 12

insufficient indirect evidence that, in patients with CP or ARP, management would change after

genetic testing in a manner likely to improve health outcomes. The evidence is insufficient to

determine the effects of the technology on health outcomes.

For individuals who are asymptomatic with family members with HP who receive testing for a

known familial variant associated with HP, the evidence includes a very limited number of

studies. Relevant outcomes are test accuracy, symptoms, change in disease status, morbid

events, and hospitalizations. No direct evidence was identified comparing outcomes in patients

tested or not tested for a familial variant. It is possible that at-risk relatives who are identified

with a familial variant may alter lifestyle factors (eg, diet, smoking, alcohol use), and this might

delay or prevent CP onset. However, studies evaluating behavioral changes and impact on

disease are lacking. The evidence is insufficient to determine the effects of the technology on

health outcomes.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in December 2017 did not identify any ongoing or unpublished

trials that would likely influence this review.

Clinical Input Received from Physician Specialty Societies and Academic

Medical Centers

While the various physician specialty societies and academic medical centers may provide

appropriate reviewers who collaborate with and make recommendations during this process,

input received does not represent an endorsement or position statement by the physician

specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 academic medical centers (one of which

provided 2 responses) and 2 specialty medical societies (one of which provided 2 responses)

when this policy was under review in 2014, with specific focus on testing in children. There was

consensus among reviewers that genetic testing for HP is medically necessary in children.

http://www.clinicaltrials.gov/

Page | 8 of 12

Practice Guidelines and Position Statements

American College of Gastroenterology

The American College of Gastroenterologys 2013 guidelines on management of acute

pancreatitis (AP) included the following statement: genetic testing may be considered in young

patients (

Page | 9 of 12

Medicare National Coverage

There is no national coverage determination (NCD). In the absence of an NCD, coverage

decisions are left to the discretion of local Medicare carriers.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory

service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the

Clinical Laboratory Improvement Amendments (CLIA). Genetic testing for hereditary pancreatitis

is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for

high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to

require any regulatory review of this test.

References

1. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. Jun 2013;144(6):1252-1261.

PMID 23622135

2. Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut. Nov 2004;53(11):1710-1717. PMID 15479696

3. Solomon S, Whitcomb DC, LaRusch J. PRSS1-Related Hereditary Pancreatitis. In: Adam MP, Ardinger HH, Pagon RAW, S.E., et al.,

eds. GeneReviews. Seattle, WA: University of Washington; 2012.

4. Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. Jun

2007;36(2):325-333, ix. PMID 17533082

5. Whitcomb DC. Framework for interpretation of genetic variations in pancreatitis patients. Front Physiol. 2012;3:440. PMID

23230421

6. Rosendahl J, Witt H, Szmola R, et al. Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with

chronic pancreatitis. Nat Genet. Jan 2008;40(1):78-82. PMID 18059268

7. ARUP Laboratories, Laboratory Test Directory. Pancreatitis, Panel (CFTR, CTRC, PRSS1, SPINK1) Sequencing. n.d.;

http://ltd.aruplab.com/tests/pub/2010876 Accessed April 2018.

8. Prevention Genetics. Chronic Pancreatitis Sequencing Panel. n.d.;

https://www.preventiongenetics.com/testInfo.php?sel=test&val=Chronic+Pancreatitis+Sequencing+Panel Accessed

April 2018.

9. Ambry Genetics. Pancreatitis Panel. n.d.; http://www.ambrygen.com/clinician/genetic-testing/69/exome-and-general-

genetics/pancreatitis-panel Accessed April 2018.

http://ltd.aruplab.com/tests/pub/2010876https://www.preventiongenetics.com/testInfo.php?sel=test&val=Chronic+Pancreatitis+Sequencing+Panelhttp://www.ambrygen.com/clinician/genetic-testing/69/exome-and-general-genetics/pancreatitis-panelhttp://www.ambrygen.com/clinician/genetic-testing/69/exome-and-general-genetics/pancreatitis-panel

Page | 10 of 12

10. AmbryGenetics. PancNext. n.d.; http://www.ambrygen.com/clinician/genetic-testing/34/oncology/pancnext Accessed

April 2018.

11. Applebaum-Shapiro SE, Finch R, Pfutzer RH, et al. Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-

Center Pancreatic Study Group Study. Pancreatology. Jul 2001;1(5):439-443. PMID 12120221

12. Ceppa EP, Pitt HA, Hunter JL, et al. Hereditary pancreatitis: endoscopic and surgical management. J Gastrointest Surg. May

2013;17(5):847-856; discussion 856-847. PMID 23435738

13. Vue PM, McFann K, Narkewicz MR. Genetic mutations in pediatric pancreatitis. Pancreas. Aug 2016;45(7):992-996. PMID

26692446

14. Saito N, Suzuki M, Sakurai Y, et al. Genetic analysis of Japanese children with acute recurrent and chronic pancreatitis. J Pediatr

Gastroenterol Nutr. Oct 2016;63(4):431-436. PMID 27409067

15. Koziel D, Gluszek S, Kowalik A, et al. Genetic mutations in SPINK1, CFTR, CTRC genes in acute pancreatitis. BMC Gastroenterol.

Jun 23 2015;15:70. PMID 26100556

16. Schwarzenberg SJ, Bellin M, Husain SZ, et al. Pediatric chronic pancreatitis is associated with genetic risk factors and substantial

disease burden. J Pediatr. Apr 2015;166(4):890-896 e891. PMID 25556020

17. Poddar U, Yachha SK, Mathias A, et al. Genetic predisposition and its impact on natural history of idiopathic acute and acute

recurrent pancreatitis in children. Dig Liver Dis. Aug 2015;47(8):709-714. PMID 25981744

18. Masson E, Chen JM, Audrezet MP, et al. A conservative assessment of the major genetic causes of idiopathic chronic

pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS

One. Aug 2013;8(8):e73522. PMID 23951356

19. Wang W, Sun XT, Weng XL, et al. Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in

Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study. BMJ Open. Sep 3 2013;3(9):e003150. PMID

24002981

20. Sultan M, Werlin S, Venkatasubramani N. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr

Gastroenterol Nutr. May 2012;54(5):645-650. PMID 22094894

21. Gasiorowska A, Talar-Wojnarowska R, Czupryniak L, et al. The prevalence of cationic trypsinogen (PRSS1) and serine protease

inhibitor, Kazal type 1 (SPINK1) gene mutations in Polish patients with alcoholic and idiopathic chronic pancreatitis. Dig Dis Sci.

Mar 2011;56(3):894-901. PMID 20676769

22. Joergensen MT, Brusgaard K, Cruger DG, et al. Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a

population-based cohort study in Denmark. Am J Gastroenterol. Aug 2010;105(8):1876-1883. PMID 20502448

23. Rebours V, Boutron-Ruault MC, Schnee M, et al. The natural history of hereditary pancreatitis: a national series. Gut. Jan

2009;58(1):97-103. PMID 18755888

24. Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. Oct

2006;33(3):221-227. PMID 17003641

25. Truninger K, Kock J, Wirth HP, et al. Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis.

Pancreas. Jan 2001;22(1):18-23. PMID 11138965

26. Culetto A, Bournet B, Haennig A, et al. Prospective evaluation of the aetiological profile of acute pancreatitis in young adult

patients. Dig Liver Dis. Jul 2015;47(7):584-589. PMID 25861839

27. Bellin MD, Freeman ML, Gelrud A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis:

recommendations from PancreasFest. Pancreatology. Jan-Feb 2014;14(1):27-35. PMID 24555976

28. Chinnakotla S, Radosevich DM, Dunn TB, et al. Long-term outcomes of total pancreatectomy and islet auto transplantation for

hereditary/genetic pancreatitis. J Am Coll Surg. Apr 2014;218(4):530-543. PMID 24655839

29. Teich N, Mossner J. Hereditary chronic pancreatitis. Best Pract Res Clin Gastroenterol. Jan 2008;22(1):115-130. PMID 18206817

http://www.ambrygen.com/clinician/genetic-testing/34/oncology/pancnext

Page | 11 of 12

30. Mullhaupt B, Truninger K, Ammann R. Impact of etiology on the painful early stage of chronic pancreatitis: a long-term

prospective study. Z Gastroenterol. Dec 2005;43(12):1293-1301. PMID 16315124

31. Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin

Gastroenterol Hepatol. Mar 2004;2(3):252-261. PMID 15017610

32. Paolini O, Hastier P, Buckley M, et al. The natural history of hereditary chronic pancreatitis: a study of 12 cases compared to

chronic alcoholic pancreatitis. Pancreas. Oct 1998;17(3):266-271. PMID 9788540

33. Hu C, Wen L, Deng L, et al. The differential role of human cationic trypsinogen (PRSS1) p.R122H mutation in hereditary and

nonhereditary chronic pancreatitis: a systematic review and meta-analysis. Gastroenterol Res Pract. Oct 8 2017;2017:9505460.

PMID 29118810

34. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J

Gastroenterol. Sep 2013;108(9):1400-1415; 1416. PMID 23896955

35. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier

screening. Genet Med. Mar-Apr 2001;3(2):149-154. PMID 11280952

36. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of

Medical Genetics mutation panel. Genet Med. Sep-Oct 2004;6(5):387-391. PMID 15371902

37. Ellis I, Lerch MM, Whitcomb DC, et al. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent

and privacy issues. Pancreatology. Jul 2001;1(5):405-415. PMID 12120217

History

Date Comments 10/14/13 New Policy. Policy created with literature review through June 30th, 2013. Genetic

testing for hereditary pancreatitis is considered investigational.

07/23/14 Update Related Policies. Remove 12.04.91.

12/08/14 Annual Review. Policy statement added for medically necessary genetic testing for

patients 18 years and younger with recurrent acute or chronic pancreatitis; all other

indications remain investigational. Policy updated with clinical input. References 6-7,

16, 18-19, and 27-28 added. Policy statement added as noted. CPT code 81222

removed; it does not apply to this policy. CPT codes 81223, 81401, and 81479 added.

11/10/15 Annual Review. Policy updated with literature review through July 8, 2015; references

6-9 and 20-22 added. Appendix Table 1 added. Policy statements unchanged.

11/01/16 Annual Review, approved October 11, 2016. Policy updated with literature review;

reference 39 added. Policy statements unchanged. Supportive language added for

application of this policy to those aged 18 and younger.

05/01/17 Annual Review, approved April 11, 2017. Policy updated with literature review through

December 20, 2016. References1, 9, 12-14, and 32 added. The policy revised with

updated genetics nomenclature. Appendix table removed. Policy statements

unchanged.

Page | 12 of 12

Date Comments 09/22/17 Policy moved into new format. No changes to policy statements.

05/01/18 Annual Review, approved April 3, 2018. Policy updated with literature review through

December 2017; reference 10 and 33 added; references 3, 9, and 36 updated. Policy

statements unchanged.

Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The

Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and

local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review

and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit

booklet or contact a member service representative to determine coverage for a specific medical service or supply.

CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). 2018 Premera

All Rights Reserved.

Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when

determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to

the limits and conditions of the member benefit plan. Members and their providers should consult the member

benefit booklet or contact a customer service representative to determine whether there are any benefit limitations

applicable to this service or supply. This medical policy does not apply to Medicare Advantage.

037338 (07-2016)

Discrimination is Against the Law Premera Blue Cross complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. Premera does not exclude people or treat them differently because of race, color, national origin, age, disability or sex. Premera: Provides free aids and services to people with disabilities to communicate

effectively with us, such as: Qualified sign language interpreters Written information in other formats (large print, audio, accessible

electronic formats, other formats) Provides free language services to people whose primary language is not

English, such as: Qualified interpreters Information written in other languages

If you need these services, contact the Civil Rights Coordinator. If you believe that Premera has failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with: Civil Rights Coordinator - Complaints and Appeals PO Box 91102, Seattle, WA 98111 Toll free 855-332-4535, Fax 425-918-5592, TTY 800-842-5357 Email AppealsDepartmentInquiries@Premera.com You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, the Civil Rights Coordinator is available to help you. You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights, electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: U.S. Department of Health and Human Services 200 Independence Avenue SW, Room 509F, HHH Building Washington, D.C. 20201, 1-800-368-1019, 800-537-7697 (TDD) Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html. Getting Help in Other Languages This Notice has Important Information. This notice may have important information about your application or coverage through Premera Blue Cross. There may be key dates in this notice. You may need to take action by certain deadlines to keep your health coverage or help with costs. You have the right to get this information and help in your language at no cost. Call 800-722-1471 (TTY: 800-842-5357). (Amharic): Premera Blue Cross 800-722-1471 (TTY: 800-842-5357)

:(Arabic) .

Premera Blue Cross. . . . (TTY: 800-842-5357) 1471-722-800

(Chinese): Premera Blue Cross

800-722-1471 (TTY: 800-842-5357)

Oromoo (Cushite): Beeksisni kun odeeffannoo barbaachisaa qaba. Beeksisti kun sagantaa yookan karaa Premera Blue Cross tiin tajaajila keessan ilaalchisee odeeffannoo barbaachisaa qabaachuu dandaa. Guyyaawwan murteessaa taan beeksisa kana keessatti ilaalaa. Tarii kaffaltiidhaan deeggaramuuf yookan tajaajila fayyaa keessaniif guyyaa dhumaa irratti wanti raawwattan jiraachuu dandaa. Kaffaltii irraa bilisa haala taeen afaan keessaniin odeeffannoo argachuu fi deeggarsa argachuuf mirga ni qabaattu. Lakkoofsa bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa. Franais (French): Cet avis a d'importantes informations. Cet avis peut avoir d'importantes informations sur votre demande ou la couverture par l'intermdiaire de Premera Blue Cross. Le prsent avis peut contenir des dates cls. Vous devrez peut-tre prendre des mesures par certains dlais pour maintenir votre couverture de sant ou d'aide avec les cots. Vous avez le droit d'obtenir cette information et de laide dans votre langue aucun cot. Appelez le 800-722-1471 (TTY: 800-842-5357). Kreyl ayisyen (Creole): Avi sila a gen Enfmasyon Enptan ladann. Avi sila a kapab genyen enfmasyon enptan konsnan aplikasyon w lan oswa konsnan kouvti asirans lan atrav Premera Blue Cross. Kapab genyen dat ki enptan nan avi sila a. Ou ka gen pou pran kk aksyon avan sten dat limit pou ka kenbe kouvti asirans sante w la oswa pou yo ka ede w avk depans yo. Se dwa w pou resevwa enfmasyon sa a ak asistans nan lang ou pale a, san ou pa gen pou peye pou sa. Rele nan 800-722-1471 (TTY: 800-842-5357). Deutsche (German): Diese Benachrichtigung enthlt wichtige Informationen. Diese Benachrichtigung enthlt unter Umstnden wichtige Informationen bezglich Ihres Antrags auf Krankenversicherungsschutz durch Premera Blue Cross. Suchen Sie nach eventuellen wichtigen Terminen in dieser Benachrichtigung. Sie knnten bis zu bestimmten Stichtagen handeln mssen, um Ihren Krankenversicherungsschutz oder Hilfe mit den Kosten zu behalten. Sie haben das Recht, kostenlose Hilfe und Informationen in Ihrer Sprache zu erhalten. Rufen Sie an unter 800-722-1471 (TTY: 800-842-5357). Hmoob (Hmong): Tsab ntawv tshaj xo no muaj cov ntshiab lus tseem ceeb. Tej zaum tsab ntawv tshaj xo no muaj cov ntsiab lus tseem ceeb txog koj daim ntawv thov kev pab los yog koj qhov kev pab cuam los ntawm Premera Blue Cross. Tej zaum muaj cov hnub tseem ceeb uas sau rau hauv daim ntawv no. Tej zaum koj kuj yuav tau ua qee yam uas peb kom koj ua tsis pub dhau cov caij nyoog uas teev tseg rau hauv daim ntawv no mas koj thiaj yuav tau txais kev pab cuam kho mob los yog kev pab them tej nqi kho mob ntawd. Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau ua koj hom lus pub dawb rau koj. Hu rau 800-722-1471 (TTY: 800-842-5357). Iloko (Ilocano): Daytoy a Pakdaar ket naglaon iti Napateg nga Impormasion. Daytoy a pakdaar mabalin nga adda ket naglaon iti napateg nga impormasion maipanggep iti apliksayonyo wenno coverage babaen iti Premera Blue Cross. Daytoy ket mabalin dagiti importante a petsa iti daytoy a pakdaar. Mabalin nga adda rumbeng nga aramidenyo nga addang sakbay dagiti partikular a naituding nga aldaw tapno mapagtalinaedyo ti coverage ti salun-atyo wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti daytoy nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357). Italiano (Italian): Questo avviso contiene informazioni importanti. Questo avviso pu contenere informazioni importanti sulla tua domanda o copertura attraverso Premera Blue Cross. Potrebbero esserci date chiave in questo avviso. Potrebbe essere necessario un tuo intervento entro una scadenza determinata per consentirti di mantenere la tua copertura o sovvenzione. Hai il diritto di ottenere queste informazioni e assistenza nella tua lingua gratuitamente. Chiama 800-722-1471 (TTY: 800-842-5357).

(Japanese): Premera Blue Cross

800-722-1471 (TTY: 800-842-5357) (Korean): . Premera Blue Cross . . . . 800-722-1471 (TTY: 800-842-5357) . (Lao): . Premera Blue Cross. . . . 800-722-1471 (TTY: 800-842-5357). (Khmer):

Premera Blue Cross

800-722-1471 (TTY: 800-842-5357) (Punjabi): . Premera Blue Cross . . , , 800-722-1471 (TTY: 800-842-5357).

:(Farsi) .

. Premera Blue Cross .

. .

)800-842-5357 TTY( 800-722-1471 .

Polskie (Polish): To ogoszenie moe zawiera wane informacje. To ogoszenie moe zawiera wane informacje odnonie Pastwa wniosku lub zakresu wiadcze poprzez Premera Blue Cross. Prosimy zwrcic uwag na kluczowe daty, ktre mog by zawarte w tym ogoszeniu aby nie przekroczy terminw w przypadku utrzymania polisy ubezpieczeniowej lub pomocy zwizanej z kosztami. Macie Pastwo prawo do bezpatnej informacji we wasnym jzyku. Zadzwocie pod 800-722-1471 (TTY: 800-842-5357). Portugus (Portuguese): Este aviso contm informaes importantes. Este aviso poder conter informaes importantes a respeito de sua aplicao ou cobertura por meio do Premera Blue Cross. Podero existir datas importantes neste aviso. Talvez seja necessrio que voc tome providncias dentro de determinados prazos para manter sua cobertura de sade ou ajuda de custos. Voc tem o direito de obter esta informao e ajuda em seu idioma e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).

Romn (Romanian): Prezenta notificare conine informaii importante. Aceast notificare poate conine informaii importante privind cererea sau acoperirea asigurrii dumneavoastre de sntate prin Premera Blue Cross. Pot exista date cheie n aceast notificare. Este posibil s fie nevoie s acionai pn la anumite termene limit pentru a v menine acoperirea asigurrii de sntate sau asistena privitoare la costuri. Avei dreptul de a obine gratuit aceste informaii i ajutor n limba dumneavoastr. Sunai la 800-722-1471 (TTY: 800-842-5357). P (Russian): . Premera Blue Cross. . , , . . 800-722-1471 (TTY: 800-842-5357). Faasamoa (Samoan): Atonu ua iai i lenei faasilasilaga ni faamatalaga e sili ona taua e tatau ona e malamalama i ai. O lenei faasilasilaga o se fesoasoani e faamatala atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua atu i ai. Faamolemole, ia e iloilo faalelei i aso faapitoa oloo iai i lenei faasilasilaga taua. Masalo o lea iai ni feau e tatau ona e faia ao lei aulia le aso ua taua i lenei faasilasilaga ina ia e iai pea ma maua fesoasoani mai ai i le polokalame a le Malo oloo e iai i ai. Oloo iai iate oe le aia tatau e maua atu i lenei faasilasilaga ma lenei famatalaga i legagana e te malamalama i ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471 (TTY: 800-842-5357). Espaol (Spanish): Este Aviso contiene informacin importante. Es posible que este aviso contenga informacin importante acerca de su solicitud o cobertura a travs de Premera Blue Cross. Es posible que haya fechas clave en este aviso. Es posible que deba tomar alguna medida antes de determinadas fechas para mantener su cobertura mdica o ayuda con los costos. Usted tiene derecho a recibir esta informacin y ayuda en su idioma sin costo alguno. Llame al 800-722-1471 (TTY: 800-842-5357). Tagalog (Tagalog): Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na walang gastos. May karapatan ka na makakuha ng ganitong impormasyon at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471 (TTY: 800-842-5357). (Thai): Premera Blue Cross 800-722-1471 (TTY: 800-842-5357) (Ukrainian): . Premera Blue Cross. , . , , . . 800-722-1471 (TTY: 800-842-5357). Ting Vit (Vietnamese): Thng bo ny cung cp thng tin quan trng. Thng bo ny c thng tin quan trng v n xin tham gia hoc hp ng bo him ca qu v qua chng trnh Premera Blue Cross. Xin xem ngy quan trng trong thng bo ny. Qu v c th phi thc hin theo thng bo ng trong thi hn duy tr bo him sc khe hoc c tr gip thm v chi ph. Qu v c quyn c bit thng tin ny v c tr gip bng ngn ng ca mnh min ph. Xin gi s 800-722-1471 (TTY: 800-842-5357).