Version July 2025
INTRODUCTION —
This monograph summarizes the interpretation of germline testing of the CTNNA1 gene, which encodes alpha catenin. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately [1].
OVERVIEW
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Determining the genotype – Identifies variants. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or comparable accreditation body in other jurisdictions, if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).
●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for a variant of uncertain significance (VUS).
The table provides a glossary of genetic testing terms (table 2).
Disease associations — The CTNNA1 gene encodes catenin alpha-1 (sometimes called alpha-catenin), which mediates cell-cell adhesion by connecting cadherin proteins at the cell surface with the underlying actin cytoskeleton. Alpha-catenin is one of three catenins (alpha, beta, and gamma) that form a catenin complex.
Gastric cancer — Pathogenic variants in CTNNA1 can lead to diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate (DGLBC; previously called hereditary diffuse gastric cancer [HDGC] syndrome), an autosomal dominant disorder. However, most cases of DGLBC are due to pathogenic variants in CDH1, which encodes cadherin 1 (also called epithelial cadherin [E-cadherin]), the main cadherin on epithelial cells. (See "Gene test interpretation: CDH1 (gene for cadherin 1)".)
DGLBC is an inherited form of diffuse-type gastric cancer, a highly invasive tumor.
●Penetrance and age of onset for diffuse-type gastric cancer in individuals with a pathogenic CTNNA1 variant are uncertain. However, intramucosal foci of diffuse gastric cancer have been found in prophylactic gastrectomy specimens from affected individuals, suggesting that these individuals are at risk for DGLBC and warrant at least endoscopic surveillance or definitive prophylactic gastrectomy [2-4].
●Analysis of CTNNA1 variants from commercial multigene panel testing suggests that the penetrance for gastric cancer may be lower than expected, although specific variants may have a significant risk for early-onset diffuse gastric cancer [4]. (See "Diffuse gastric and lobular breast cancer syndrome", section on 'Management of carriers of CTNNA1 variants'.)
Breast cancer (not clearly increased) — Unlike DGLBC syndrome due to a pathogenic variant in CDH1, which carries an increased risk for invasive lobular breast cancer (ILBC), the risk of ILBC in individuals with pathogenic variants in CTNNA1 has not definitively been established.
IMPLICATIONS OF THE RESULT
Pathogenic or likely pathogenic variant — We consider all individuals with a pathogenic or likely pathogenic variant in CTNNA1 to be at risk for diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate (DGLBC; previously called hereditary diffuse gastric cancer [HDGC] syndrome), regardless of the initial reason for testing. Discussion should include the range of associated risks, possible interventions for cancer surveillance or risk reduction, and implications for family members. (See 'At-risk relatives' below.)
We adhere to guidelines by the International Gastric Cancer Linkage Consortium (IGCLC) for cancer surveillance and risk reduction [5]. Findings in relatives (type of cancers, age of onset) may also inform surveillance. As an example, if a relative developed gastric cancer at an earlier age than screening was scheduled, it may be prudent to perform screening at this younger age.
Evaluations and interventions to reduce the risk of cancers associated with DGLBC syndrome include (algorithm 1):
●Gastric cancer – At a minimum, asymptomatic carriers of pathogenic or likely pathogenic CTNNA1 variants should undergo counseling, risk assessment, and yearly surveillance endoscopy in an expert center. (See "Diffuse gastric and lobular breast cancer syndrome", section on 'Management of carriers of CTNNA1 variants'.)
•Endoscopy – Annual screening, starting at age 18, with an upper endoscopy with biopsies (Cambridge protocol) to screen for gastric cancer. Endoscopy should be performed in a center of expertise.
-Individuals who carry a pathologic CTNNA1 variant should be screened for infection with Helicobacter pylori (H. pylori) and treated if positive. (See "Helicobacter pylori: Diagnosis and management in the pediatric patient" and "Indications and diagnostic tests for Helicobacter pylori infection in adults" and "Treatment of Helicobacter pylori infection in adults".)
-Individuals who chose surveillance upper endoscopy to screen for gastric cancer should be informed that there is no reliable endoscopic screening test for the early diagnosis of diffuse gastric cancer. Gastric cancers that arise in patients with DGLBC are signet ring cancers that are located beneath an intact surface epithelium and only become visible on direct mucosal evaluation later in the disease process. (See "Diffuse gastric and lobular breast cancer syndrome", section on 'Management of carriers of CTNNA1 variants'.)
•Gastrectomy – We individualize decision-making about prophylactic gastrectomy in the context of the penetrance of gastric cancer in the kindred.
Individuals with signet ring cells or diffuse gastric cancer on gastric biopsy should undergo total gastrectomy. (See "Surgical management of invasive gastric cancer".)
●Breast cancer – Although the frequency of invasive lobular breast cancer in individuals with pathogenic variants in CTNNA1 appears low, a comprehensive breast cancer risk assessment should be performed [6]. Depending on personal and family history of breast cancer of any type, referral to a high-risk breast cancer clinic may be appropriate with intensification of surveillance and individualized decision-making on the benefits of risk-reducing mastectomy or chemoprevention. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CDH1 (Hereditary diffuse gastric cancer syndrome)' and 'Breast cancer (not clearly increased)' above and "Diffuse gastric and lobular breast cancer syndrome", section on 'Management of carriers of CTNNA1 variants' and "Factors that modify breast cancer risk in females".)
Negative test or benign variant — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes (eg, CDH1).
●If a familial CTNNA1 variant is known and the tested individual does not have that variant, usually they can be reassured that they are not at increased risk for DGLBC syndrome, with caveats outlined above (see 'How to read the report' above). However, it is important to provide an individualized risk assessment based on family history and other risk factors.
●If a familial CTNNA1 variant is not known and the results of genetic testing are negative, the extent of additional testing depends on the personal and family history. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to guide additional genetic testing based on the personal and family history. Intensive endoscopic screening may be considered in patients who meet DGLBC criteria. (See 'Locating an expert' below.)
Variant of uncertain significance (VUS) — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history.
Annual endoscopic surveillance for gastric cancer is suggested in patients with a CTNNA1 VUS for at least two years, ideally as part of a research study [5].
Female patients with a CTNNA1 VUS should receive individualized breast cancer risk assessment and surveillance recommendations (algorithm 1).
New information on a VUS may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually).
The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary cancer syndromes may be appropriate.
CONSIDERATIONS FOR RELATIVES
Reproductive counseling — Reproductive counseling is appropriate for individuals with a pathogenic or likely pathogenic CTNNA1 variant who are considering childbearing.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
At-risk relatives — Individuals with a pathogenic variant or likely pathogenic variant in CTNNA1 should inform their at-risk relatives about the importance of genetic counseling and possible testing.
Testing is generally deferred to adulthood to allow proper informed consent. An exception is if relatives had gastric cancer during late childhood, which is rare, in which case testing should be near the age the affected relative was diagnosed with cancer. Considerations in the genetic testing of children are presented separately. (See "Genetic testing", section on 'Testing children'.)
●If the disease-causing variant is present in a first-degree relative (parent, child, sibling), the risk of having inherited the variant is 50 percent for the tested individual.
●Usually, the disease-causing variant is inherited from the side of the family with a history of gastric cancer. If possible, it is recommended to an affected individual (individual with gastric cancer) first to identify the specific genetic variant, followed by cascade testing of other relatives.
RESOURCES
UpToDate topics
●DGLBC syndrome – (See "Diffuse gastric and lobular breast cancer syndrome" and "Surgical management of gastric cancer in patients with DGLBCS".)
●Genetics:
•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Locating an expert
●Patient advocacy organization (No Stomach For Cancer)
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
