When a patient who would not normally be recommended for CDH1 genetic testing — that is, someone without a family history of gastric cancer — undergoes genetic testing with a multigene panel that includes detection of CDH1, the results can be difficult to interpret.

Patients may learn that they carry a pathogenic CDH1 variant, which is associated with hereditary diffuse gastric cancer syndrome — and although the gastric cancer risk is unclear in the absence of a family history, this information may lead to a clinician recommending risk-reducing total gastrectomy.

Total gastrectomy can lead to long-term morbidity, including having dumping syndrome, weight loss, and nutritional and metabolic complications.

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Therefore, the discovery of an “unexpected” CDH1 variant on a multigene panel test in the absence of a family history of gastric cancer can create a “difficult conundrum” for clinicians and patients, the authors of a commentary published in the Journal of the National Cancer Institute explained.1

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“These challenging situations are being increasingly encountered in practice,” the authors revealed, noting that CDH1 is included on “many” commonly ordered cancer-focused multigene panels.

The concern with unexpected CDH1 variants is there are “considerable” uncertainties regarding CDH1 variants and their management. Specifically, the degree of gastric cancer risk associated with CDH1 variants in patients without a family history of gastric cancer is “uncertain.” Furthermore, there is uncertainty about the cancer risk of specific CDH1 variants and “limited understanding” of the factors that promote progression of small foci of signet ring cell carcinoma to diffuse gastric cancer in CDH1 carriers.

Despite these uncertainties, excluding CDH1 from multigene panels may not be a long-term solution because of the increased time and labor burdens imposed on genetic counselors, the authors of a corresponding editorial wrote.2

Instead, as the commentary authors propose, patients should be informed of the uncertainties surrounding CDH1 during pretest counseling, as well as told that if a CDH1 variant is discovered, risk-reducing total gastrectomy is the “near-global” recommendation.


  1. Katona BW, Clark DF, Domchek SM. CDH1 on multigene panel testing: Look before you leap. J Natl Cancer Inst. doi: 10.1093/jnci/djz229
  2. Stewart DR, Frone MF, Chanock SJ. Stomaching multigene panel testing: What to do about CDH1? [published online December 16, 2019] J Natl Cancer Inst. doi: 10.1093/jnci/djz230