MEDICAL POLICY
POLICY
RELATED POLICIES
POLICY GUIDELINES
CODING
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
APPENDIX
HISTORY
Genetic Testing for Hereditary Pancreatitis
Number
Effective Date
Revision Date(s)
Replaces
12.04.99
May 1, 2017
05/01/17; 11/01/16; 11/10/15; 12/08/14; 07/23/14
2.04.99
Policy
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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.
Genetic testing for hereditary pancreatitis is considered investigational in all other situations.
Related Policies
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None
Policy Guidelines
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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 individual’s 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.
Coding
81223
81401
CPT
CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene
sequence
Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically
81404
81479
using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)
Includes the following tests:

PRSS1 (protease, serine, 1 [trypsin 1]) (e.g., hereditary pancreatitis), common variants (e.g., N29I,
A16V,R122H)
Molecular pathology procedure, Level 5 (e.g., 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]) (e.g., hereditary pancreatitis), full gene sequence, SPINK1 (serine
peptidase inhibitor, Kazal type 1) (e.g., hereditary pancreatitis), full gene sequence
Unlisted molecular pathology
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 Rationale section for more detail.
Description
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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 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 trypsin activation within the pancreas, resulting in autodigestion,
inflammation, elevation of pancreatic enzymes in 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 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
hereditary pancreatitis (HP), especially early in the course of the disease. HP is a rare disorder; in 1997 there
were about 1,000 people with HP in the United States.(1)
Genetic Determinants of Hereditary Pancreatitis (HP)
PRSS1 Variant
Whitcomb et al discovered that variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause
HP. PRSS1 encodes cationic trypsinogen. Gain of function variants of the PRSS1 gene cause HP by prematurely
and excessively converting trypsinogen to trypsin, which then results in pancreatic autodigestion. Between 60%
and 80% of people who have a PRSS1 variant will experience pancreatitis in their lifetimes; 30% to 40% will
develop CP. Most, but not all, people with a variantvariant of PRSS1 will have inherited it from one of their
parents. The proportion of HP caused by a spontaneous variant of PRSS1 is unknown. In families with two or
more affected individuals in two or more generations, genetic testing shows that most have a demonstrable
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 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 posttest 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)
CTRC Variants
CTRC is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W and p.K247_R254del)
are associated with 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. Ambry’s PancNext™ panel consists of NGS of 13 genes: APC, ATM, BRCA1, BRCA2, CDKN2A,
EPCAM, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53.(9)
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratorydeveloped 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.
Scope
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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.
Benefit Application
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N/A
Rationale
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This policy was created in August 2013 and updated periodically with literature reviews, most recently through
December 20, 2016.
Validation of the clinical use of any genetic test focuses on 3 main principles: (1) analytic validity, which refers to
the technical accuracy of a test in detecting a variant that is present or in excluding a variant that is absent; (2)
clinical validity, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative
predictive values) in detecting clinical disease; and (3) clinical utility (ie, how the results of a diagnostic test will be
used to change management of the patient and whether these changes in management lead to clinically
important improvements in health outcomes). Following is a summary of the key literature.
Genetic Testing For Hereditary Pancreatitis In Patients With Chronic Pancreatitis Or
Recurrent Acute Pancreatitis
Clinical Context and Test Purpose
The purpose of genetic testing of patients who have chronic pancreatitis (CP) or acute recurrent pancreatitis
(ARP) is to confirm a diagnosis and inform management decisions.
The question addressed in this evidence review is: Does genetic testing improve health outcomes in individuals
with CP or ARP?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients with chronic pancreatitis or recurrent acute pancreatitis.
Interventions
Genetic testing for hereditary pancreatitis (HP).
Comparators
Standard clinical management without genetic testing.
Outcomes
The general outcomes of interest are test accuracy, symptoms, change in disease status, morbid events and
hospitalizations.
Time
The time frame for outcome measurement varies from short-term development of symptoms to long-term survival
outcomes. There are no clear established frameworks to use for outcome timeframes.
Setting
Patients are generally referred by a family practice physician or gastroenterologist to a medical geneticist.
Referral for genetic counseling is important for explanation of genetic disease, heritability, genetic risk, test
performance, and possible outcomes
Analytic Validity
Testing for variants in the protease, serine, 1 (trypsin 1) (PRSS1), serine peptidase inhibitor (SPINK), and cystic
fibrosis (CF) transmembrane conductance regulator (CFTR) genes is usually done by direct sequence analysis,
which is the criterion standard for detecting a variant that is present and/or excluding a variant that is absent.
Testing can also be done by next-generation sequencing, which has an accuracy that approaches that of direct
sequencing. In patients who test negative by either of these methods, duplication/deletion analysis may be
performed to detect copy number variations. These genetic testing methods are considered to have high analytic
validity.
Clinical Validity
The clinical validity of genetic testing for hereditary pancreatitis (HP) refers to the variant detection rate in patients
who have known HP.
There is a lack of published evidence on the percent of patients who are first identified as having clinically defined
HP and then tested for genetic variants. Most studies that examine the variant detection rate use a population of
patients with idiopathic chronic pancreatitis (CP) and do not necessarily require that patients have a family history
of CP. In other studies, cohorts of patients with HP were defined by the presence of genetic variants or family
history, which therefore may include patients with genetic variants who do not have a family history of CP.
A summary of representative studies reporting the sensitivity and specificity of genetic testing in patients with is
included in Table 1.
Table 1. Summary of Studies Reporting the Clinical Validity of HP Gene Testing
Study
Applebaum-Shapiro
(2001) (U.S.)(10)
Ceppa (2013)
(U.S.)(11)
Patients with CP and/or
ARP
Vue (2016)
(U.S.)(12)
Population
115 patients with HP defined
clinically
87 patients with HP, defined by
known pathogenic variant or family
history
Genes Tested
PRSS1
Detection Rate
52% (60/115)
PRSS1,
SPINK,
CFTR
62% (54/87)
91 children with ARP (n=77) or CP
(n=14)
SPINK, CFTR,
PRESS1,
33/69 (48%) tested had at least 1
disease-associated variant
Saito (2016)
(Japan)(13)
128 children with CP or ARP
Koziel (2015)
(Poland)(14)
221 patients with AP and 345
healthy controls
Schwarzenberg (2015)
(international)(15)
170 children, 76 with CP and 94
with ARP
Poddar (2015)
(India)(16)
68 children with pancreatitis
(35.3% AP, 32.3% ARP, 32.3%
CP); 25 healthy controls
253 patients with idiopathic CP
Masson (2013)
(France)(17)
Wang (2013)
(China)(18)
75 children with idiopathic CP
Sultan (2012)
(U.S.)(19)
29 children with ARP or CP
Gasiorowska (2011)
(Poland)(20)
Joergensen (2010)
(Denmark)(21)
14 patients with idiopathic CP; 46
control patients without pancreatitis
122 patients with idiopathic
pancreatitis
Rebours (2009)
(France)(22)
Keiles (2006)
(U.S.)(23)
200 patients with CP
Truninger (2001)
(Germany)(24)
104 patients with CP
389 patients with recurrent or CP
referred for genetic testing
PRSS1,
SPINK,
CTRC, CPA1
SPINK, CFTR,
CTRC
PRSS1,
SPINK,
CFTR, CTRC
PRSS1,
SPINK, CFTR
39.1% (50/128) had at least 1
abnormal variant
 Variants identified:
SPINK (6.3% of AP, 3.2% controls)
 CFTR (2.3% of AP, 3.8% of
controls)
CTRC (1.8% of AP, 1.2% of controls)
67% (51/76) with CP
44% (38/68)
PRSS1,
SPINK,
CFTR, CTRC
PRSS1,
SPINK,
CFTR, CTRC,
CLDN2
PRSS1,
SPINK,
CFTR
PRSS1,
SPINK
PRSS1,
SPINK,
CFTR
PRSS1
 23.7% (60/253) “causal” variant
24.5% (62/253) “contributory” variant
PRSS1,
SPINK,
CFTR
PRSS1
49% (185/381)
66.7% (50/75) (with PRSS1 or SPINK
variants)
79% (23/29)
50% (7/14)
40% (49/122)
68% (136/200)
8% (8/104)
AP: acute pancreatitis; ARP: acute recurrent pancreatitis; CP: chronic pancreatitis; HP: hereditary pancreatitis.
Only 2 studies were identified that included patients with known HP. Applebaum-Shapiro et al (2001) identified
PRSS1 variants in 52% of patients with HP; other patients may have had different disease-associated variants not
addressed in this study.(10 Ceppa et al (2013) identified PRSS1, SPINK, or CFTR disease-associated variants in
62% of patients with HP. Again, other patients may have had different, rarer, variants.(11)
The true clinical sensitivity and specificity for genetic testing in cases of HP are uncertain for a number of reasons.
First, the populations in published studies have been defined differently, with most not consisting of patients with
clinically defined HP. The populations are from different geographic regions, in which the prevalence of genetic
variants may vary. Some of the studies have mixed adult and pediatric populations, while others have reported on
either adults or children. Finally, genes tested for in these studies have differed, with many studies not including
all of the known genes associated with HP.
At least 1 study (2015) found that the proportion of patients with acute pancreatitis attributable to genetic causes
is higher among younger patients. In a group of 309 subjects with acute pancreatitis, patients ages 35 and
younger (n=66) were more likely to have a genetic cause of pancreatitis identified (10%) than older patients
(1.5%; p=0.003).(25)
Section Summary
A number of studies have reported variant detection rates in various populations of patients with CP, but few
studies have enrolled a population of patients with known HP. Studies that tested patients with known HP
reported detection rates between 52% and 62%; studies may not have tested for all relevant genetic variants. For
other studies that tested patients with CP or ARP, disease-associated variant detection rates varied widely across
studies.
Clinical Utility
Direct Evidence
There are no direct outcome data on the clinical utility of testing for confirmation of HP (ie, no studies have
reported outcomes data for patients tested and not tested for HP).
Chain of Evidence
A chain of evidence would evidence that genetic testing can identify individuals with HP who would not otherwise
be identified, that treatments are available for these patients that would not otherwise be given to patients with CP
or ARP, and that these treatments improve health outcomes.
There is some evidence that testing patients with HP, or patients with CP or ARP, can identify individuals with
disease-associated variants (see Clinical Validity section). However, it is unclear whether patient management
would differ for patients with CP depending on whether or not a variant associated with HP is found. Conservative
therapy for CP includes a low-fat diet with multiple small meals, maintenance of good hydration, use of
antioxidants, and avoidance of smoking and alcohol use. While all of these interventions may alter the natural
history of the disease, there is no evidence that the impact differs for HP compared with other etiologies of CP.
Moreover, there is a lack of evidence that treatments (eg, for CP-related pain) would differ depending on whether
or not patients had HP. Total pancreatectomy with islet cell transplantation (or total pancreatectomy with islet
autotransplantation [TP-IAT]) has been investigated in CP or ARP, particularly as a treatment for intractable pain
in patients with impaired quality of life in whom medical, endoscopic, or prior surgical treatment have failed.
However, questions remain about the best timing of surgery, selection of candidates, evaluation of outcomes, and
follow-up.(26) Chinnakotla et al (2014) retrospectively compared outcomes after TP-IAT for patients with HP or
familial pancreatitis compared with other causes of CP among 484 patients treated at a single institution from
1977 to 2012, 80 of whom had HP.(27) Genetic testing was not available for all patients with suspected HP.
Multiple causes of HP or familial pancreatitis were included: 38 with PRSS1 variants; 9 with SPINK1 variants; 14
with CFTR variants; and 19 with familial pancreatitis without a variant specified. Patients with HP were younger at
the time of TP-IAT (mean age, 21.9 years vs 37.9 years in nonhereditary CP, p<0.001), but had a longer history of
pancreatitis (mean, 10.1 years vs 6.4 years in nonhereditary CP, p<0.001). Pain scores significantly improved
after TP-IAT (p<0.001), with no significant differences between HP and nonhereditary CP.
Several studies were identified that examined whether the severity and/or natural history of CP differs in patients
with and without disease-associated variants. Some have reported that patients with HP have an earlier age of
onset compared with patients with other etiologies of CP.(28) Other studies have examined whether the severity
and natural history differ for patients with HP, but findings have been inconsistent. Some studies have reported
that disease progression is slower in patients with HP(28-30) and that surgical intervention is required less often
for patients with HP.(29) However, 1 study also reported that the cumulative risk for exocrine failure was more
than twice as high for patients with disease-associated variants compared with patients without diseaseassociated variants.(30) In another small study (1998) that compared the clinical course of patients with HP to
those with alcoholic CP, most clinical manifestations were similar, but patients with HP had a higher rate of
pseudocysts.(31)
Section Summary
The evidence on clinical utility does not support an improvement in health outcomes associated with genetic
testing. For diagnostic testing, there is a lack of direct evidence that genetic testing leads to management
changes. A chain of evidence does not indicate that treatment would differ for patients with HP compared to other
patients with CP. In addition, the evidence to date is insufficient to determine whether patients with HP respond
differently to treatments such as TP-IAT than other patients with CP. However, there is a suggestion that patients
with HP have earlier onset of disease and inconsistent evidence on disease severity in patients with HP versus
other types of CP.
Targeted Testing Asymptomatic Relatives Of Patients With HP
Clinical Context and Test Purpose
The purpose of genetic testing of asymptomatic relatives of patients with HP is to determine the likelihood that the
individual will develop CP.
The question addressed in this evidence review is: Does genetic testing improve health outcomes in
asymptomatic relatives of patients with HP?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients who are asymptomatic with a relative or relatives who have been
diagnosed with HP.
Interventions
Genetic testing for HP.
Comparators
Standard clinical management without genetic testing.
Outcomes
The general outcomes of interest are test accuracy, symptoms, change in disease status, morbid events, and
hospitalizations.
Time
There are no clinical guidelines with recommendations for monitoring asymptomatic individuals found to have
variants associated with HP. The timeframe for outcome measurement varies from short-term development of
symptoms to long-term survival outcomes. There are no clear established frameworks to use for outcome
timeframes.
Setting
Asymptomatic patients might be referred by a family practice physician to a medical geneticist. Referral for
genetic counseling is important for explanation of genetic disease, heritability, and genetic risk.
Analytic Validity
Same as previous section for patients with CP or ARP.
Clinical Validity
Same as previous section for patients with CP or ARP.
Clinical Utility
Predictive testing can be performed in asymptomatic relatives of patients with known HP to determine the
likelihood of CP. For this population, no direct evidence was identified that compared outcomes in patients who
did and did not undergo genetic testing. It is possible that at-risk relatives who are identified with diseaseassociated variants might alter lifestyle factors (eg, diet, smoking, alcohol use), and this might delay or prevent
CP onset. However, evidence on this question is lacking, so that conclusions cannot be made on whether genetic
testing of asymptomatic family members of patients with HP improves outcomes.
Section Summary
There is a lack of evidence that genetic testing of asymptomatic relatives of patients with HP leads to
interventions that delay or prevent pancreatitis onset. It is possible that patients might alter lifestyle factors that
increase risk of pancreatitis, but studies are lacking.
Summary of Evidence
For individuals who have chronic pancreatitis (CP) or acute recurrent pancreatitis (ARP) who receive testing for
genes associated with hereditary pancreatitis (HP), the evidence includes cohort studies on variant detection
rates. 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 diseaseassociated variants between 52% and 62%. For other studies that tested patients with CP or ARP, diseaseassociated variant detection rates varied widely across studies. There is a lack of direct evidence that testing for
HP improves health outcomes, and insufficient chain of 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 co. 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 may 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.
Clinical Input Received from Physician Specialty Societies and Academic Medical
Centers
While the various physician specialty societies and academic medical centers may collaborate with and make
recommendations during this process through the provision of appropriate reviewers, 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.
Practice Guidelines and Position Statements
American College of Gastroenterology
The American College of Gastroenterology’s 2013 guidelines on management of acute pancreatitis (AP) included
the following statement: “genetic testing may be considered in young patients (<30 years old) if no cause [of AP]
is evident and a family history of pancreatic disease is present (conditional recommendation, low quality of
evidence).”(32)
American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics issued a policy statement on laboratory standards and
guidelines for population-based cystic fibrosis (CF) carrier screening in 2001,(33) which were updated in 2004(34)
and reaffirmed in 2013.(35) These guidelines have provided recommendations on specific variant testing in CF,
but have not specifically addressed genetic testing for suspected hereditary pancreatitis (HP).
European Consensus Conference
A 2001 European Consensus Conference developed guidelines for genetic testing of the PRSS1 gene, genetic
counseling, and consent for genetic testing for HP.(36) The recommended indications for symptomatic patients
included:
 Recurrent (2 or more separate, documented episodes with hyperamylasemia) attacks of acute
pancreatitis for which there is no explanation




Unexplained chronic pancreatitis
A family history of pancreatitis in a first- or second-degree relative
Unexplained pancreatitis in a child – if recurrent or requiring hospitalization
Predictive genetic testing, defined as genetic testing in an asymptomatic “at-risk” relative of an individual
proven to have HP, was considered more complex. Candidates for predictive testing should be a firstdegree relative of an individual with a well-defined HP gene variant, capable of informed consent, and
able to demonstrate an understanding of autosomal dominant inheritance, incomplete penetrance,
variable expressivity, and the natural history of HP. Written informed consent must be documented
before the genetic test is performed.
U.S. Preventive Services Task Force Recommendations
Not applicable.
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.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in January 2017 did not identify any ongoing or unpublished trials that would likely
influence this review.
References
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2013;144(6):1252-1261. PMID 23622135
2. Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut. Nov 2004;53(11):17101717. PMID 15479696
3. Solomon S, Whitcomb, D.C., LaRusch, J, et al. PRSS1-Related Hereditary Pancreatitis. GeneReviews
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 (2010876). n.d.; http://ltd.aruplab.com/tests/pub/2010876 Accessed April 2017.
8. Prevention Genetics. Chronic Pancreatitis Sequencing Panel. n.d.;
https://www.preventiongenetics.com/testInfo.php?sel=test&val=Chronic+Pancreatitis+Sequencing+Panel
Accessed April 2017.
9. Ambry Genetics. Pancreatitis Testing. n.d.; http://www.ambrygen.com/tests/pancreatitis-testing
Accessed April 2017.
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11. Ceppa EP, Pitt HA, Hunter JL, et al. Hereditary pancreatitis: endoscopic and surgical management. J
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13. 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
14. 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
15. 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
16. 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
17. 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. 2013;8(8):e73522. PMID 23951356
18. 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. 2013;3(9):e003150. PMID 24002981
19. 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
20. 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
21. 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
22. 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
23. 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
24. 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
25. 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
26. 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
27. 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
28. Teich N, Mossner J. Hereditary chronic pancreatitis. Best Pract Res Clin Gastroenterol. 2008;22(1):115130. PMID 18206817
29. 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
30. 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
31. 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
32. 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
33. 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
34. 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
35. American College of Medical Genetics and Genomics. Cystic fibrosis population carrier screening: 2004
revision of American College of Medical Genetics mutation panel. 2004 (reaffirmed 2013);
http://www.acmg.net/StaticContent/StaticPages/CF_Mutation.pdf Accessed April 2017.
36. Ellis I, Lerch MM, Whitcomb DC, et al. Genetic testing for hereditary pancreatitis: guidelines for
indications, counselling, consent and privacy issues. Pancreatology. 2001;1(5):405-415. PMID 12120217
37. BlueCross BlueShield Association (BCBSA). Genetic Testing for Hereditary Pancreatitis. Medical Policy
Reference Manual, Policy No. 2.04.99, 2017
Appendix
[TOP]
N/A
History
[TOP]
Date
10/14/13
07/23/14
12/08/14
11/10/15
11/01/16
05/01/17
Reason
New Policy. Policy created with literature review through June 30th, 2013. Genetic testing for
hereditary pancreatitis is considered investigational.
Update Related Policies. Remove 12.04.91.
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.
Annual Review. Policy updated with literature review through July 8, 2015; references 6-9 and 2022 added. Appendix Table 1 added. Policy statements unchanged.
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.
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.
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).
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លុយេឡើយ។ សូ មទូ រស័ពទ 800-722-1471 (TTY: 800-842-5357)។
ਪੰ ਜਾਬੀ (Punjabi):
ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ
ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ
ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ
ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ
ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ
800-722-1471 (TTY: 800-842-5357).
‫( فارسی‬Farsi):
‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬
‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través 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 médica o ayuda con los costos. Usted
tiene derecho a recibir esta información 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).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).