Medical Policy Medical Policy
Policy Num: 11.003.059
Policy Name: Genetic Testing for Hereditary Pancreatitis
Policy ID: [11.003.059] [Ac / B / M+ / P+] [2.04.99]
Last Review: March 10, 2025
Next Review: March 20, 2026
Related Policies: None
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals: · With chronic pancreatitis or recurrent acute pancreatitis | Interventions of interest are: · Testing for genes associated with hereditary pancreatitis | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include: · Symptoms · Change in disease status · Morbid events · Hospitalizations |
| 2 | Individuals: · Who are asymptomatic with family members with hereditary pancreatitis | Interventions of interest are: · Targeted testing for a known familial variant associated with hereditary pancreatitis | Comparators of interest are: · Standard clinical management without genetic testing | Relevant outcomes include: · Symptoms · Change in disease status · Morbid events · Hospitalizations |
In chronic pancreatitis (CP), recurrent attacks of acute pancreatitis evolve into a chronic inflammatory state with exocrine insufficiency, endocrine insufficiency manifested as diabetes, 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 variant in 1 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.
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 and meta-analyses. Relevant outcomes are 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 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 that the technology results in an improvement in the net health outcome.
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 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 as having 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 the impact on disease are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
Clinical input was sought in 2014 to determine whether genetic testing for hereditary pancreatitis (HP) for individuals who have acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice.
In response to requests, input was received from 2 specialty medical societies (1 of which provided 2 responses) and 4 academic medical centers (1 of which provided 2 responses) when this policy was under review in 2014. Input was specific to testing children. There was a consensus among reviewers that genetic testing for hereditary pancreatitis is medically necessary for children.
For individuals who have ARP or CP who receive genetic testing for HP, clinical input supports this use provides a clinically meaningful improvement in net health outcome and indicates this use is consistent with generally accepted medical practice in a subgroup of appropriately selected patients. Clinical input has supported the use of genetic testing for HP in children, despite a lack of evidence for improvements in outcomes, due to the possibility of reduced diagnostic testing in the setting of a genetically determined HP diagnosis. The following patient selection criteria are based on clinical expert opinion and information from clinical study populations: children (≤18 years) with ARP (>1 episode) or CP.
The objective of this evidence review is to evaluate whether genetic testing improves the net health outcome for individuals with chronic or recurrent pancreatitis or who have a familial risk for hereditary pancreatitis.
Genetic testing for hereditary pancreatitis may be considered medically necessary for patients aged 18 years and younger with unexplained acute recurrent (>1 episode) or chronic pancreatitis with documented elevated amylase or lipase levels.
Genetic testing for hereditary pancreatitis is considered investigational in all other situations.
The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It was implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organisation, and by the Human Genome Variation Society itself.
The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.
| Previous | Updated | Definition |
| Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
| Variant | Change in the DNA sequence | |
| Familial variant | Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives |
| Variant Classification | Definition |
| Pathogenic | Disease-causing change in the DNA sequence |
| Likely pathogenic | Likely disease-causing change in the DNA sequence |
| Variant of uncertain significance | Change in DNA sequence with uncertain effects on disease |
| Likely benign | Likely benign change in the DNA sequence |
| Benign | Benign change in the DNA sequence |
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.
Genetic counseling is primarily aimed at individuals 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.
See the Codes table for details.
Some Plans may have contract or benefit exclusions for genetic testing.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
Whitcomb (2001) discovered that disease-associated variants of protease, serine, 1 (trypsin 1) (PRSS1) on chromosome 7q35 cause hereditary pancreatitis (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 chronic pancreatitis (CP). Most, but not all, people with a disease-associated variant of PRSS1 will have inherited it from 1 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 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.1,
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.2,3, 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, a serine protease inhibitor, Kazal type 1 (SPINK1) gene, chymotrypsin C (CTRC) gene, and claudin-2 (CLDN2) gene.
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 insufficiency, and may present with acute, recurrent acute, or CP.2, Individuals with heterozygous variants of the CFTR gene (CF carriers) have a 3- to 4-fold increased risk for CP. Individuals with 2 CFTR pathogenic variants (homozygotes or compound heterozygotes) will benefit from CF-specific evaluations, therapies, and genetic counseling.
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 acute recurrent 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.4,
The CTRC gene is important for the degradation of trypsin and trypsinogen, and 2 variants (p.R254W, 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).5, Tropical pancreatitis is a disease almost exclusively occurring in the setting of tropical climate and malnutrition.
The CLDN2 gene 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 variants in CLDN2 have been associated with CP.
Testing for variants associated with HP is typically done by direct sequence analysis or next-generation sequencing. A number of 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). Genetic testing for HP 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 has chosen not to require any regulatory review of this test.
This evidence review was created in August 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through January 22, 2025.
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.
The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
Acute pancreatitis (AP) and chronic pancreatitis (CP) are caused by trypsin activation within the pancreas, resulting in autodigestion, inflammation, elevation of pancreatic enzymes in serum, and abdominal pain. is defined as a state of ongoing inflammation associated with chronic or 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. Gallstones, 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 AP in childhood and evolves into CP by age 20 years old. 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. Chronic pancreatitis is also associated with comorbidities with known racial health disparities (eg, diabetes, renal disease, obesity).
HP is associated with a markedly increased risk of pancreatic cancer, although HP patients account for a small fraction of all cases of pancreatic cancer and are only a subset of the 10% of pancreatic cancers that are considered to have a genetic or familial predisposition. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.6,
The purpose of genetic testing of patients who have CP or acute recurrent pancreatitis (ARP) is to confirm a diagnosis and inform management decisions.
The following PICO was used to select literature to inform this review.
The relevant population of interest is patients with CP or ARP.
The test being considered is genetic testing for HP.
The following practice is currently being used: standard clinical evaluation and management without genetic testing.
The general outcomes of interest are symptoms, change in disease status, morbid events, and hospitalizations. The time frame for outcomes measurement varies from the short-term development of symptoms to long-term survival outcomes. There are no clearly established frameworks to use for outcome time frames.
For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).
Included a suitable reference standard.
Patient/sample clinical characteristics were described.
Patient/sample selection criteria were described.
Included a validation cohort separate from the development cohort.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). The clinical validity of genetic testing for HP refers to the variant detection rate in patients who have known HP.
There is a lack of published evidence on the percentage of patients who are first identified as having clinically defined HP and then tested for genetic variants. Most studies that examined disease-associated variant detection rates used a population of patients with idiopathic CP and did 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 observational studies reporting rates of detecting disease-associated variants in patients with symptoms of pancreatitis is included in Table 1.
| Studies | Population | Genes Tested | Detection Rate |
| Patients with HP | |||
| Applebaum-Shapiro et al. (2001)7, (U.S.) | 115 patients with HP defined clinically | PRSS1 | 52% (60/115) |
| Ceppa et al. (2013)8, (U.S.) | 87 patients with HP, defined by known pathogenic variant or family history | PRSS1, SPINK, CFTR | 62% (54/87) |
| Patients with CP, AP or ARP | |||
| Weiss et al. (2018)9, | 1462 patients with AP and 3999 controls | PRSS1-PRSS2, RIPPLY, MORC4 | PRSS1-PRSS2: OR 0.88; 95% CI: 0.81-0.97; p=.01 RIPPLY: OR 1.27; 95% CI: 1.07-1.5; p=.005 MORC4: OR 1.32; 95% CI: 1.12-1.56; p=.001 |
| Zou et al. (2018)10, | 1061 idiopathic CP patients and 1196 controls | SPINK1, PRSS1, CTRC, CFTR | CP group: 50.42% (535/1061) Control group: 5.94% (71/1196) OR: 16.12; p<.001 (CI NR) |
| Vue et al. (2016)11, (U.S.) | 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 et al. (2016)12, (Japan) | 128 children with CP or ARP | PRSS1, SPINK, CTRC, CPA1 | 39.1% (50/128) had at least 1 abnormal variant |
| Koziel et al. (2015)(Poland)13, | 221 patients with AP and 345 healthy controls | SPINK, CFTR, CTRC | 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) |
| Schwarzenberg et al. (2015)14, (international) | 170 children, 76 with CP and 94 with ARP | PRSS1, SPINK, CFTR, CTRC | 67% (51/76) with CP |
| Poddar et al. (2015)15, (India) | 68 children with pancreatitis (35.3% AP, 32.3% ARP, 32.3% CP); 25 healthy controls | PRSS1, SPINK, CFTR | 44% (38/68) |
| Masson et al. (2013)16, (France) | 253 patients with idiopathic CP | PRSS1, SPINK, CFTR, CTRC | 23.7% (60/253) “causal” variant 24.5% (62/253) “contributory” variant |
| Wang et al. (2013)17, (China) | 75 children with idiopathic CP | PRSS1, SPINK, CFTR, CTRC, CLDN2 | 66.7% (50/75) (with PRSS1 or SPINK variants) |
| Sultan et al. (2012)18, (U.S.) | 29 children with ARP or CP | PRSS1, SPINK, CFTR | 79% (23/29) |
| Gasiorowska et al. (2011)19, (Poland) | 14 patients with idiopathic CP; 46 healthy controls | PRSS1, SPINK | 50% (7/14) |
| Joergensen et al. (2010)20, (Denmark) | 122 patients with idiopathic pancreatitis | PRSS1, SPINK, CFTR | 40% (49/122) |
| Rebours et al. (2009)21, (France) | 200 patients with CP | PRSS1 | 68% (136/200) |
| Keiles et al. (2006)22, (U.S.) | 389 patients with recurrent or CP | PRSS1, SPINK, CFTR | 49% (185/381) |
| Truninger et al. (2001)23, (Germany) | 104 patients with CP | PRSS1 | 8% (8/104) |
AP: acute pancreatitis; ARP: acute recurrent pancreatitis; CI: confidence interval; CP: chronic pancreatitis; HP: hereditary pancreatitis; NR: not reported; OR: odds ratio;
Only 2 studies were identified that evaluated patients with known HP. Applebaum-Shapiro et al. (2001) identified protease, serine, 1 (trypsin 1) (PRSS1) variants in 52% of patients with HP; other patients might have had different disease-associated variants not addressed in this study.7, Ceppa et al (2013) identified PRSS1, serine peptidase inhibitor (SPINK), or cystic fibrosis transmembrane conductance regulator (CFTR) disease-associated variants in 62% of patients with HP. Again, other patients may have had different, rarer variants.8, 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 were from different geographic regions, in which the prevalence of genetic variants may vary. Some of the studies assessed mixed adult and pediatric populations, while others reported on either adults or children. Finally, genes tested differed, with many studies not including all of the known genes associated with HP.
Culetto et al. (2015) found that the proportion of patients with AP attributable to genetic causes is higher among younger patients. In a group of 309 subjects with AP, 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=.003).24,
Weiss et al. (2018) used genetic testing to analyze associations between common variants and AP; 1462 patients with AP and 3999 healthy controls were evaluated.9, For all AP patients, significant associations were found for PRSS1-PRSS2 variant (rs10273639) (odds ratio [OR]=0.88; 95% confidence interval [CI]: 0.81-0.97; p=.01), RIPPLY variant (rs7057398) (OR=1.27; 95% CI: 1.07-1.5; p=.005), and MORC4 (rs12688220) (OR=0.32; 95% CI: 1.12-1.56; p=.001). Patients were included with AP of all etiologies and did not specifically have a history of recurrent episodes. The population was drawn from 4 European countries, and the variant identification varied in the different populations. The results confirmed that PRSS1-PRSS2 is protective. The other 2 variants are being investigated for a pathogenic phenotype.
Zou et al. (2018) analyzed 1196 controls and 1061 Han Chinese patients with idiopathic CP tested with targeted next-generation sequencing of 4 CP-associated genes (SPINK1, PRSS1, CTRC, CFTR).10, The objective of the study was to focus on rare variants defined as <1% frequency in the control population. Variants were identified in 535 (50.42%; OR=16.12; p<.001) patients with CP compared to 71 (5.94%) controls. There was also an interest in assessing the influence of a variant on clinical presentation and disease onset. Median age at disease onset differed between mutation-positive (29.7±14.84 years) and mutation-negative patients (43.01±15.97 years; p<.001). When patients were divided into idiopathic (n=715), alcoholic (n=206), and smoking-associated (n=140) CP subgroups, the rates of pathogenic genotypes were 57.1%, 39.8%, and 32.1%, respectively. The study did not assess the variants more commonly encountered, which are associated with a more defined phenotype.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).
There are no direct outcome data on the clinical usefulness of testing for confirmation of HP (ie, no studies have reported outcomes data for patients tested and not tested for HP).
A chain of evidence would demonstrate 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 above section). However, it is unclear if patient management would differ for patients with CP depending on whether 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.
There is a lack of evidence that treatments (eg, for CP-related pain) would differ depending on whether 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 treatments have failed. However, questions remain about the best timing of surgery, selection of candidates, evaluation of outcomes, and follow-up.25, Chinnakotla et al (2014) retrospectively compared outcomes after TP-IAT for patients who had HP or familial pancreatitis with other causes of CP among 484 patients treated at a single institution from 1977 to 2012, 80 of whom had HP.26, 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<.001), but had a long history of pancreatitis (mean, 10.1 years vs. 6.4 years in nonhereditary CP, p<.001). Pain scores significantly improved after TP-IAT (p<.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. A 2008 review article reported that patients with HP have an earlier age of onset compared with patients with other etiologies of CP.27, Other studies have reported data from an observational cohort and a registry that disease progression is slower in patients with HP27,28,29, and that surgical intervention is required less often for patients with HP.28, The registry 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 disease-associated variants.29, A small case series (1998) compared the clinical course of patients who had HP with those who had alcoholic CP.30, Most clinical manifestations were similar, but patients with HP had a higher rate of pseudocysts.
A systematic review and meta-analysis by Hu et al (2017) investigated the association between the p.R122H variant in the PRSS1 gene and the risk of CP.31, Eight case-control studies in which patients had CP, either hereditary or of another cause, were included. Analysis of all 8 reviewed studies (n=1733 patients with CP of all etiologies combined; n=2415 controls) showed an overall pooled OR of 4.78 (95% CI: 1.13 to 20.20); heterogeneity was low (I2=32.2%). A subgroup analysis compared hereditary CP with nonhereditary CP in 4 studies (n=225 patients, n=2214 controls). There was low heterogeneity between the studies (p=.235; I2=29.5%), with a pooled OR for an association between the p.R122H variant and the risk of hereditary CP of 65.52 (95% CI: 9.09 to 472.48). By comparison, the pooled OR for an association between the p.R122H variant and an increased risk of nonhereditary CP was 2.79 (95% CI: 0.68 to 1.55).
Takáts et al (2022) conducted a meta-analysis evaluating the association between loss-of-function CTRC variants (p.A73T, p.V235I, p.K247_R254del, and p.R254W) and CP (of various etiologies).32, Fourteen studies met inclusion criteria. All 4 variants were found more frequently in CP patients than controls: p.A73T (OR, 6.5; 95% CI, 2.4 to 17.8), p.V235I (OR, 4.5; 95% CI, 2.2 to 9.1), p.K247_R254del (OR, 5.4; 95% CI, 2.6 to 11.0), and p.R254W (OR, 2.6; 95% CI, 1.6 to 4.2). The authors estimated that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3- to 7-fold.
There is an increased risk for pancreatic cancer in individuals with CP caused by HP. Individuals with HP have an estimated 40% to 55% lifetime risk of developing pancreatic cancer.6, The risk estimates are primarily derived from the study of populations diagnosed with clinical evaluation and family history and antedate characterizations based on genetic variant status. These risk estimates may also represent populations with higher smoking prevalence rates. Smoking increases the likelihood of developing pancreatic cancer in all populations. In general, pancreatic cancer is diagnosed at late stages and has very low 5-year survival rates. The lack of specificity of premalignant signs and symptoms and uncertainties about the most appropriate imaging or diagnostic studies to assess pancreatic lesions limit the opportunity to make an earlier diagnosis. However, evidence-informed consensus guidelines and opinions have recently appeared to screen for pancreatic cancer in individuals at high risk. (See Supplemental Information.)
A number of studies have reported variant detection rates in various populations of patients with CP, but there is limited frequency information on populations of patients with known HP. Studies that tested patients with known HP reported variant detection rates between 52% and 62%. Genotype-phenotype studies have attempted to characterize rarer variants as well as determine the influence of variant status on clinical presentation and disease onset. Multiple observational studies tested patients with AP or ARP, with variant detection rates varying widely. These studies have added information to the variant frequency differences in populations and subgroups. The published 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 with 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 an earlier onset of disease and inconsistent evidence on disease severity in patients with HP versus other types of CP. A systematic review and meta-analysis identified 8 studies that included patients with CP of several etiologies and found an increased association between the presence of the PRSS1 gene p.R122H variant in both hereditary and nonhereditary CP, and a meta-analysis of CTRC loss-of-function variants indicated an association of these variants with CP.
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 and meta-analyses. Relevant outcomes are 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 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 that the technology results in an improvement in the net health outcome.
Clinical input has supported the use of genetic testing for HP in children, despite a lack of evidence for improvements in outcomes, due to the possibility of reduced diagnostic testing in the setting of a genetically determined HP diagnosis. As a result, genetic testing for HP in children (≤18 years) with ARP (>1 episode) or CP may be considered medically necessary.
| [X] MedicallyNecessary | [ ] Investigational |
The purpose of genetic testing of asymptomatic relatives of patients with HP is to determine the likelihood that the individual will develop CP.
The following PICO was used to select literature to inform this review.
The relevant population of interest is patients who are asymptomatic with a relative or relatives who have been diagnosed with HP.
The test being considered is genetic testing for HP.
The following practice is currently being used: no genetic testing for HP.
The general outcomes of interest are symptoms, change in disease status, morbid events, and hospitalizations. There are no clinical guidelines with recommendations for testing asymptomatic relatives of a patient with HP or for monitoring asymptomatic individuals if found to have variants associated with HP. The time frame for outcome measurement varies from the short-term development of symptoms to long-term survival outcomes. There are no clearly established frameworks to use for outcome time frames.
For the evaluation of the clinical validity of the tests, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores).
Included a suitable reference standard.
Patient/sample clinical characteristics were described.
Patient/sample selection criteria were described.
Included a validation cohort separate from the development cohort.
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse). Another aspect of clinical validity for HP genetic testing refers to the variant detection rate in patients who have family members with HP.
There is a lack of published evidence on the percentage of asymptomatic patients who are tested for HP genetic variants.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
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 disease-associated 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 conclusions cannot be made on whether genetic testing of asymptomatic family members of patients with HP improves outcomes.
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 lifestyle interventions might alter the risk of subsequent pancreatitis but such studies are lacking.
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 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 as having 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 the impact on disease are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
| [ ] MedicallyNecessary | [X] Investigational |
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
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.
Clinical input was sought to determine whether genetic testing for hereditary pancreatitis (HP) for individuals who have acute recurrent pancreatitis (ARP) or chronic pancreatitis (CP) would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice.
In response to requests, input was received from 2 specialty medical societies (1 of which provided 2 responses) and 4 academic medical centers (1 of which provided 2 responses) when this policy was under review in 2014. Input was specific to testing children. There was a consensus among reviewers that genetic testing for hereditary pancreatitis is medically necessary for children.
For individuals who have ARP or CP who receive genetic testing for HP, clinical input supports this use provides a clinically meaningful improvement in net health outcome and indicates this use is consistent with generally accepted medical practice in a subgroup of appropriately selected patients. Clinical input has supported the use of genetic testing for HP in children, despite a lack of evidence for improvements in outcomes, due to the possibility of reduced diagnostic testing in the setting of a genetically determined HP diagnosis. The following patient selection criteria are based on clinical expert opinion and information from clinical study populations: children (≤18 years) with ARP (>1 episode) or CP.
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
In 2013, the American College of Gastroenterology (ACG) guidelines on management of acute pancreatitis included the following statement: “Genetic testing may be considered in young patients (<30 years old) if no cause [of acute pancreatitis] is evident, and a family history of pancreatic disease is present (conditional recommendation, low quality of evidence).”33,
In 2015, the ACG Clinical Guideline: Genetic Testing and Management of Hereditary Gastrointestinal Cancer Syndromes recommended genetic testing of patients with suspected familial pancreatic cancer to include analysis of BRCA1/2, CDKN2A, PALB2, and ATM. Evaluation for Peutz-Jeghers Syndrome, Lynch Syndrome, and HP-associated genes should be considered if personal and/or family history criteria are met for the syndrome.34,
The 2020 ACG guidelines for CP include the following recommendation for genetic testing in CP: "We recommend genetic testing in patients with clinical evidence of a pancreatitis-associated disorder or possible CP in which the etiology is unclear, especially in younger patients (strong recommendation, low quality of evidence)."35, The goal of genetic testing is "to identify underlying pancreatitis-related disorders that are contributing to the pathogenic process, to assist in decision making, and to help prevent the development of irreversible CP." The guidelines include the following genetic polymorphisms related to CP: PRSS, CPA1, CEL, SPINK1, CTRC, CFTR, CASR, and CLDN2; however, the guidelines recommend (at a minimum) testing for PRSS1, SPINK1, CFTR, and CTRC gene mutations in patients with idiopathic CP.
In 2014, the American Pancreatic Association published Practice Guidelines in Chronic Pancreatitis: Evidence-Based Report on Diagnostic Guidelines.36, A classification guideline for the etiology of CP includes genetic mutations in PRSS1, CFTR, SPINK1, and others.
In 200137, (updated in 2004)38,; reaffirmed in 201339,), the American College of Medical Genetics and Genomics (ACMG) issued a policy statement on laboratory standards and guidelines for population-based cystic fibrosis carrier screening. These guidelines provided recommendations on specific variant testing in cystic fibrosis but did not specifically address genetic testing for suspected HP. In 2020, a technical standard on CFTR variant testing by the ACMG was released.40, The standard stated that indications for CFTR variant testing included diagnosis and carrier testing for individuals with idiopathic pancreatitis.
In 2018, the working group for the International Consensus Guidelines for Chronic Pancreatitis, in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group, and the European Pancreatic Club, published consensus statements on the diagnosis and management of early CP.41, It included the following recommendation:
“Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (Quality assessment: moderate; Recommendation: strong; Agreement: strong)”
There was an update to the guideline in 2020, and it included the following statement: 42,
"In idiopathic disease, full sequence analysis of the CFTR, CPA1, CTRC, PRSS1 and SPINK1 gene exons and exon-intron boundaries and testing for the CEL gene pathogenic hybrid allele is recommended in order to explore the genetic background. (Quality assessment: low; Recommendation: conditional; Agreement: conditional)."
In 2017, the International Study Group of Pediatric Pancreatitis INSPPIRE (The International Study Group of Pediatric Pancreatitis: In search for a cuRE) consortium developed an expert consensus opinion on the evaluation of children with acute recurrent and chronic pancreatitis.43, There was a strong consensus that search for a genetic cause of acute recurrent pancreatitis or CP should include PRSS1, SPINK1, CFTR, and CTRC gene mutation testing.
In 2018, the American Society of Clinical Oncology (ASCO) published “Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion”.44, The ASCO reported that cancer-unaffected individuals should be offered genetic risk evaluation if they are members of families with an identified pathogenic cancer susceptibility gene variant, from families that meet criteria for genetic evaluation for known hereditary syndromes that are linked to pancreatic cancer, and from families that meet criteria for familial pancreatic cancer. ASCO further considered what surveillance strategies should be used for individuals with a predisposition to pancreatic ductal adenocarcinoma to screen for pancreatic and other cancers. Surveillance can be considered for individuals who are first-degree relatives of individuals with familial pancreatic cancer and/or individuals with a family history of pancreatic cancer who carry a pathogenic germline variant in genes associated with predisposition to pancreatic cancer.
The National Comprehensive Cancer Network (NCCN) released guidelines (v.2.2024 ) on genetic/familial high-risk assessment for breast, ovarian, and pancreatic cancers.45, The NCCN recommends "germline testing for PRSS1, SPINK1, and other pancreatitis genes in individuals with a personal and/or family history of exocrine pancreatic cancer only if there is a personal and/or family history suggestive of hereditary pancreatitis." In individuals with pathogenic or likely pathogenic variants in PRSS1 or other hereditary pancreatitis genes and a clinical phenotype consistent with hereditary pancreatitis, NCCN recommends considering pancreatic cancer screening 20 years after onset of pancreatitis, or at age 40 years, whichever is earlier.
Not applicable.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
A search of ClinicalTrials.gov in January 2025 did not identify any ongoing or unpublished trials that would likely influence this review.
| Codes | Number | Description |
|---|---|---|
| CPT | 81220 | CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines) |
| 81221 | CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants | |
| 81222 | CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants | |
| 81223 | CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence | |
| 81401 | Molecular pathology procedure, Level 2; PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) | |
| 81404 | Molecular pathology procedure, Level 5; 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. | |
| 81405 | Molecular pathology procedure, Level 6; CTRC (chymotrypsin C) (eg, hereditary pancreatitis), full gene sequenc | |
| 81479 | Unlisted molecular pathology procedure | |
| ICD-10-CM | K85.00-K85.92 | Acute pancreatitis code range |
| K86.1 | Other chronic pancreatitis | |
| ICD-10-PCS | Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. | |
| Type of service | Laboratory | |
| Place of service | Reference Laboratory |
As per Correct Coding Guidelines
| Date | Action | Description |
| 03/10/25 | Annual Review | Policy updated with literature review through January 22, 2025; no references added. Policy statements unchanged. |
| 03/11/24 | Annual Review | Policy updated with literature review through January 22, 2024; no references added. Policy statements unchanged. |
| 03/14/23 | Annual Review | Policy updated with literature review through December 13, 2022; references added. Minor editorial refinements to policy statements; intent unchanged. Promotion of greater diversity and inclusion in clinical research paragraph was added. |
| 03/15/22 | Annual Review | Policy updated with literature review through December 14, 2021; references added. Practice guidelines updated. Policy statements unchanged. |
| 03/19/21 | Annual Review | Policy updated with literature review through December 10, 2020; no references added. Policy statements unchanged. |
| 03/11/20 | Annual Review | Policy updated with literature review through December 9, 2019; no references added. Policy statements unchanged. |
| 02/11/20 | Annual Review | No change |
| 02/11/19 | Annual Review | No change |
| 02/02/18 | Annual Review | No change |