Gene test interpretation: CTNNA1

INTRODUCTION — This monograph summarizes the interpretation of germline testing of the CTNNA1 gene. 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 hereditary diffuse gastric cancer [HDGC] syndrome).

●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of uncertain significance (VUS).

The table provides a glossary of genetic testing terms (table 2).

Disease associations — The CTNNA1 gene encodes alpha-1 catenin which plays an important role in the cell adhesion process by connecting cadherin proteins which are located on the cell surface and promote cell-cell adhesion. Pathogenic variants in CTNNA1 can lead to HDGC syndrome, an autosomal dominant disorder. However, most cases of HDGC are due to pathogenic variants in the tumor suppressor gene, CDH1, encoding cadherin 1, the epithelial cell-cell adhesion protein.

Gastric cancer — HDGC is an inherited form of diffuse-type gastric cancer, a highly invasive tumor. Penetrance for diffuse-type gastric cancer in individuals with a pathogenic CTNNA1 variant and the age of onset are uncertain. However, intramucosal foci of diffuse gastric cancer have been found in prophylactic gastrectomy specimens from affected individuals [2-4], suggesting that these individuals are at risk for HDGC and warrant at least endoscopic surveillance or definitive prophylactic gastrectomy. 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 "Hereditary diffuse gastric cancer", section on 'Carriers of CTNNA1 pathogenic or likely pathogenic variants'.)

Breast cancer — Unlike individuals with HDGC syndrome due to a pathogenic variant in CDH1 who are at 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 A PATHOGENIC OR LIKELY PATHOGENIC VARIANT — We consider all individuals with a pathogenic or likely pathogenic variant in CTNNA1 to be at risk for 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 family members (type of cancers, age of onset) may also inform surveillance.

Evaluations and interventions to reduce the risk of cancers associated with HDGC syndrome include (algorithm 1):

●Gastric cancer

•Annual screening 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 mutation should be screened for infection with Helicobacter pylori (H. pylori) and treated if positive. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults", section on 'Diagnostic tests' and "Treatment regimens for Helicobacter pylori in adults", section on 'Initial antibiotic therapy'.)

•We individualize decision-making about prophylactic gastrectomy in the context of the penetrance of HDGC in the family. At the very least, asymptomatic carriers of pathogenic or likely pathogenic CTNNA1 variants should undergo counseling, risk assessment, and yearly surveillance endoscopy in an expert center. (See "Hereditary diffuse gastric cancer", section on 'Carriers of CTNNA1 pathogenic or likely pathogenic variants'.)

•Patients who chose to undergo 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 HDGC 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 "Hereditary diffuse gastric cancer", section on 'Carriers of CTNNA1 pathogenic or likely pathogenic variants'.)

•Patients with signet ring cells or diffuse gastric cancer on gastric biopsy should undergo total gastrectomy. (See "Surgical management of invasive gastric cancer".)

●Breast cancer – The risk of invasive lobular breast cancer in individuals with pathogenic variants in CTNNA1 is unclear. A comprehensive breast cancer risk assessment should be performed. Depending on personal and family history of cancer, 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' above and "Hereditary diffuse gastric cancer", section on 'Carriers of CTNNA1 pathogenic or likely pathogenic variants' and "Factors that modify breast cancer risk in women".)

IMPLICATIONS OF A NEGATIVE TEST — 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 hereditary diffuse gastric cancer (HDGC) 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 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 HDGC criteria. (See 'Locating an expert' below.)

IMPLICATIONS OF A 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]. Women with a CTNNA1 VUS should receive individualized breast cancer risk assessment and surveillance recommendations (algorithm 1).

New information on VUSs may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually). (See "Hereditary diffuse gastric cancer", section on 'Surveillance for breast cancer'.)

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 FAMILY MEMBERS

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.

●If the disease-causing variant in the family is not a de novo variant, the risk of having inherited the variant is 50 percent for first-degree relatives, including siblings and parents; if one parent carries the variant, then the risk to siblings is also 50 percent. Others at risk may include aunts, uncles, nieces, nephews, and cousins.

●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 test a parent or other relative with cancer.

●Generally, predictive genetic testing is undertaken in adulthood; however, genetic testing may be appropriate to consider as early as mid- to late adolescence depending on an earlier age of onset for diffuse gastric cancer in the family. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications of a pathogenic or likely pathogenic variant' above.)

RESOURCES

UpToDate topics

●Hereditary diffuse gastric cancer (HDGC) syndrome – (See "Hereditary diffuse gastric cancer" and "Surgical management of hereditary diffuse gastric cancer".)

●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

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●National Institutes of Health (NIH) Cancer Genetics Services Directory