Germline Genetic Testing for Hereditary Diffuse Gastric Cancer (CDH1, CTNNA1)

POLICY NUMBER

A.2.04.154

DESCRIPTION

Hereditary Diffuse Gastric Cancer (HDGC, sometimes called signet ring gastric cancer) is an autosomal dominant syndrome characterized by the development of diffuse gastric cancers. CDH1 is a tumor suppressing gene that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing HDGC and lobular breast cancer. Testing for CTNNA1 variants has also been proposed for individuals with or at risk for HDGC. Knowledge of variant status in individuals at potentially increased risk may impact health care decisions to reduce risk.

Hereditary Diffuse Gastric Cancer

Hereditary Diffuse Gastric Cancer (HDGC, sometimes called signet ring gastric cancer) is an autosomal dominant syndrome primarily characterized by an increased lifetime risk of diffuse gastric cancer (DGC). The condition is rare. In the general U.S. population, the lifetime risk of developing gastric cancer is 0.8%. Approximately 20% of all gastric cancers are DGCs, and 1% to 3% of these are due to HDGC (approximately 5 to 10 per 100,000 births). The incidence of HDGC is estimated at 5 to 10 per 100,000 births. The diffuse type of gastric cancer is difficult to diagnose on upper endoscopy and as a result, most cases of DGC are diagnosed at late stages. The average age at diagnosis is 37 years. The 5-year relative survival is 7.0% for gastric cancer that has metastasized, compared to 75.4% for localized gastric cancer.

Cadherin-1 Gene CDH1

CDH1 is a tumor suppressing gene located on chromosome 16q22.1 that encodes the cell-to-cell adhesion protein E-cadherin. Germline variants in the CDH1 gene have been associated with an increased risk of developing HDGC and lobular breast cancer. A diagnosis of HDGC can be confirmed by genetic testing, although 20% to 40% of families with suspected HDGC do not have a CDH1 variant on genetic testing. Pathogenic CDH1 variants have been described in Maori families in New Zealand, and individuals of Maori ethnicity have a higher prevalence of diffuse-type gastric cancer than non-Maori New Zealanders. Therefore, guidelines include Maori ethnicity as a risk factor for HDGC. Cleft lip/palate has been described in some HDGC families and is also included in CDH1 genetic testing guidelines.

Catenin alpha 1 Gene CTNNA1

CTNNA1, which encodes the protein Catenin Alpha-1, is a suspected tumor suppressor and susceptibility gene for HDGC.

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). Germline genetic testing for CDH1 variants 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.

Related medical policies –

• Germline Genetic Testing for Hereditary Breast/Ovarian Cancer Syndrome and Other High-Risk Cancers (BRCA1, BRCA2, PALB2)

• Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes

POLICY

Germline genetic testing for CDH1 variants to identify individuals with or at risk for hereditary diffuse gastric cancer (HDGC) may be considered medically necessary for individuals meeting the following criteria (see Policy Guidelines):

• A diagnosis of diffuse gastric cancer (DGC) before age 50 years; OR

• A diagnosis of DGC at any age in individuals of Maori ethnicity, or with a personal or family history of cleft/lip palate; OR

• A diagnosis of bilateral lobular breast cancer before age 70 years; OR

• Personal or family history of both DGC and lobular breast cancer, one diagnosed before age 70 years; OR

• Two 1st- or 2nd-degree relatives (see Policy Guidelines) with a diagnosis of gastric cancer at any age, one DGC; OR

• Two 1st- or 2nd-degree relatives (see Policy Guidelines) with a diagnosis of lobular breast cancer before 50 years of age.

Germline genetic testing for CDH1 variants in individuals not meeting the above criteria is considered investigational.

Germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC is considered investigational (see Policy Guidelines).

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic v3. 2025 recommend testing for high-penetrant breast cancer susceptibility genes including CDH1 for individuals diagnosed at any age with lobular breast cancer with personal or family history of diffuse gastric cancer and state, "See NCCN Guidelines for Gastric Cancer." Thus, these two NCCN guidelines' criteria conflict as to the age of lobular breast cancer.

1st-degree relatives are parents, siblings, and children.

2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.

Testing Strategy

• In individuals with a known familial CDH1 variant, targeted testing for the specific variant is recommended.

• In individuals with unknown familial CDH1 variant:

• • To identify clinically significant variants, National Comprehensive Cancer Network (NCCN) advises testing a close relative (see above) who has cancer related to hereditary diffuse gastric cancer syndrome, because that individual has the highest likelihood of obtaining a positive test result. Testing family members without a related cancer diagnosis could be considered if family members with a related cancer are unwilling or unavailable for testing.

• The International Gastric Linkage Consortium recommends germline genetic testing for CTNNA1 variants to identify individuals with or at risk for HDGC who meet criteria for CDH1 testing and have had CDH1 testing with no CDH1 variant identified. Consideration could be given to targeted testing at-risk family members when a CTNNA1 variant has been previously identified in a close family member. However, the evidence on follow-up of asymptomatic CTNNA1 mutation carriers who had small diffuse gastric cancer foci found on prophylactic gastrectomy is based on very limited sample size and it is not known if those findings would have led to invasive cancer. Without additional study of long-term follow-up with endoscopic surveillance and large cohort studies there is risk of unneeded prophylactic gastrectomy.

Testing Unaffected Individuals

• In unaffected family members of potential CDH1 variant families, most test results will be negative and uninformative. Therefore, it is strongly recommended that an affected family member be tested first whenever possible to adequately interpret the test. Should a CDH1 variant be found in an affected family member(s), DNA from an unaffected family member can be tested specifically for the same variant of the affected family member without having to sequence the entire gene. Interpreting test results for an unaffected family member without knowing the genetic status of the family may be possible in the case of a positive result for an established disease-associated variant but leads to difficulties in interpreting negative test results (uninformative negative) or variants of uncertain significance because the possibility of a causative CDH1 variant is not ruled out.

Testing Minors

• The use of genetic testing for CDH1 variants for identifying hereditary diffuse gastric cancer syndrome has limited or no clinical utility in minors because there is no change in management for minors as a result of knowledge of the presence or absence of a deleterious variant. In addition, there are potential harms related to stigmatization and discrimination. Exceptions to this might be based on family history and/or high risk ethnicity.

Genetics Nomenclature Update

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 is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, 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 2 shows the recommended standard terminology- "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign"- to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

ACMG-AMP: American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Genetic Counseling

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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

08/01/2023: New policy added. Approved by the Medical Policy Advisory Committee.

09/12/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding NCCN guidelines.

09/12/2024: Policy description updated regarding new data for hereditary diffuse gastric cancer. Policy statements unchanged. Policy Guidelines updated.

12/31/2024: Code Reference section updated to revise description for CPT codes 81432 and 81435 effective 01/01/2025.

09/17/2025: Policy description updated. Policy statements unchanged. Policy Guidelines updated.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes C50.A0, C50.A1, and C50.A2.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.154

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.