CDH1-Related Cancer Risk

The CDH1 gene is a tumor suppressor protein, which means it helps to regulate cells so that they don’t grow out of control or grow too rapidly.

The CDH1 gene has been described as a highly penetrant cancer predisposition gene meaning that there is a significantly increased risk for certain types of gastric (stomach) and breast cancer. The associated type of breast cancer is called lobular breast cancer; and the associated type of stomach cancer is called diffuse/ signet ring gastric cancer.

CDH1 cancer screening and risk-reducing options

As CDH1 is considered a highly penetrant gene, the NCCN recommends breast cancer screening with annual mammogram and breast MRI starting at the age of 30 years.  Screening may be recommended earlier in patients with a family history of early onset breast cancer.  The option for risk-reducing mastectomy may also be considered by female carriers of CDH1 mutations.

At this time, upper endoscopies have not been proven to effectively identify diffuse gastric cancer at early stages. Given the significant risk of diffuse gastric cancer in individuals with CDH1 mutations, a multidisciplinary approach should be taken in the consideration and recommendation for prophylactic gastrectomy.


CDH1 testing in other family members

At this point in time, genetic testing in family members after age 20 years of age is generally accepted and recommended, but maybe adjusted based on psychosocial and family history factors. It is recommended that concerned family members discuss the issue of genetic testing with their physicians.  If an adult family member were to test positive for the familial CDH1 gene mutation, increased cancer screening and risk reduction surgical options could be considered.

Significance of pathogenic or likely pathogenic CDH1 mutations

When pathogenic (harmful) or likely pathogenic (likely harmful) changes (mutations) are detected in CDH1, this information is informative in 4 ways:

  1. Diagnostics: It might have contributed to a cancer developing and provides part of an explanation as to why someone develops cancer.
  2. Prevention: If identified in other family members, early screening or risk reducing surgies might be indicated and pursued.
  3. Therapeutics: The CDH1 gene produces a protein in the body essential for cell adhesion, migration and cellular turnover and if this function is altered, a cell may be unstable and develop into a cancer. Clinical trials for individuals with CDH1 mutations may exist or open in the future.
  4. Family Planning: Some individuals and families may decide to use genetic information for planning a family.  It is important to know that for CDH1 mutation carriers, there is a 50% risk for an offspring to also inherit the mutation.

Variants of uncertain significance (VUS) in the CDH1 gene

VUS should not prompt management, therapeutic or family decision making. Consultation with a clinical genetics specialist is recommended.

Variant Repositories for CDH1 gene variants

The federal government is invested in learning more about variants of uncertain significance and tracking these variants in a central source called ClinVar.  However, significant expertise and curation is required before variants are deposited in this central source. PROMPT is dedicated to generating quality data.

The consequences of misclassification can be significant and costly when individuals make life impacting decisions.  Recently, the PROMPT study team illustrated in work spearheaded by Balamana et al. how different variants may be classified and the potential consequences of mis-classification based on the 4 main uses of this information by individuals and providers.

CDH1 Resources/Literature

More information on the CDH1 gene:

Gene Information:   OMIM: 192090 , GeneTests, Orphanet, DECIPHER

Where to send testing: Genetic Testing Registry

Catalogue of mutations:  ClinVar

Registry information: PROMPT


1.  Kaurah P, MacMillan A, Boyd N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA 2007;297:2360–2372

2.  Vogelaar et al. JMG. doi:10.1136/jmedgenet-2015-103094

3.  Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001;121:1348–1353.

4.  Walsh MF, Nathanson KL, Couch FJ, Offit K. Adv Exp Med Biol. 2016;882:1-32. Genomic Biomarkers for Breast Cancer Risk. doi: 10.1007/978-3-319-22909-6