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.
For individuals without suspected hereditary diffuse gastric cancer (HDGC) who are at risk for HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are overall survival (OS), disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of CDH1 testing in asymptomatic individuals. Penetrance estimates for gastric cancer range from 42% to 70% in men and 33% to 56% in women. Penetrance is higher in individuals from families with more gastric cancer cases and is lower in individuals identified by methods such as multigene panel testing. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of prophylactic total gastrectomy (PTG) to reduce risk of gastric cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with suspected HDGC who receive germline genetic testing for CDH1 variants, the evidence includes retrospective observational studies. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There are no targeted treatments for HDGC based on CDH1 variant status. The benefit of genetic testing to affected individuals would be to inform healthcare decisions to reduce risk of other cancers, and to inform decisions about genetic testing for at-risk family members. A chain of evidence can be established from studies demonstrating an association between CDH1 variant status and increased risk of developing HDGC or lobular breast cancer, and the availability of PTG to reduce risk of gastric cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals with suspected HDGC, or without suspected HDGC who are at risk for HDGC who receive germline genetic testing for CTNNA1 variants, the evidence includes a small number of case reports of CTNNA1 variants identified in individuals from families with HDGC. Relevant outcomes are OS, disease-specific survival, test validity, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity. There is no direct evidence of the clinical utility of testing for CTNNA1 variants in individuals with suspected HDGC or at risk for HDGC. The evidence is insufficient to demonstrate clinical validity and therefore a chain of evidence cannot be established. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
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):
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).
| CPT | 81406 | Includes CDHI full gene sequence (cadherin 1, type 1, E-cadherin [epithelial]) (eg, hereditary diffuse gastric cancer) |
| 81432 | Hereditary breast cancer-related disorders (eg, hereditary breast cancer, hereditary ovarian cancer, hereditary endometrial cancer); genomic sequence analysis panel, must include sequencing of at least 10 genes, always including BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, PALB2, PTEN, STK11, and TP53 | |
| 81435 | Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1, MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11 | |
| 81479 | Unlisted molecular pathology procedure (use for CTNNA1 gene) |
| ICD10 CM | C16.0- C16.9 | Malignant Neoplasm of Stomach code range |
| C50.011- C50.929 | Malignant Neoplasm of Breast code range | |
| D05.00- D05.02 | Lobular Carcinoma in-situ of Breast code range | |
| Z15.01 | Genetic susceptibility to malignant neoplasm of breast | |
| Z15.09 | Genetic susceptibility to other malignant neoplasm | |
| Z80.0 | Family history of malignant neoplasm of digestive organs | |
| Z85.00- Z85.09 | Personal history of malignant neoplasm code range | |
| Z86.000 | Personal history of in-situ neoplasm of breast | |
| Z87.730 | Personal history of (corrected) cleft lip and palate |
Plans may need to alter local coverage medical policy to conform to state law regarding coverage of biomarker testing. The National Comprehensive Cancer Network (NCCN) guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic v.3.20232024 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. Plans with legislative mandated coverage of biomarkers might need to use the broader criteria for coverage determination.
1st-degree relatives are parents, siblings, and children.
2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings.
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, NCCN advises testing a close relative (see above) who has cancer related to hereditary diffuse gastric cancer (HDGC) 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 (Benusiglio et al, 2019). Without additional study of long-term follow-up with endoscopic surveillance and large cohort studies there is risk of unneeded prophylactic gastrectomy.
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 PG1). 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 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-AMP: American College of Medical Genetics and Genomics and the 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.
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 5.97.0% for gastric cancer that has metastasized, compared to 2875.4% for localized gastric cancer.1,
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.2,3, 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 Māori 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.
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.
