Article Text

Download PDFPDF
Original research
Simplified and more sensitive criteria for identifying individuals with pathogenic CDH1 variants
  1. Benjamin A Lerner1,
  2. Rosa M Xicola2,
  3. Nicolette J Rodriguez3,
  4. Rachid Karam4,
  5. Xavier Llor2
  1. 1 Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  2. 2 Department of Medicine and Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA
  3. 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
  4. 4 Ambry Genetics Corp, Aliso Viejo, California, USA
  1. Correspondence to Dr Xavier Llor, Department of Medicine and Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA; xavier.llor{at}


Background Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant syndrome most often caused by pathogenic variants in CDH1. The International Gastric Cancer Linkage Consortium (IGCLC) recently updated its criteria for genetic testing. The purpose of this study was to estimate the sensitivity of IGCLC’s 2020 criteria for identifying carriers of CDH1 pathogenic variants and to formulate a new set of criteria that is simpler and more sensitive.

Methods Medical histories of 112 CDH1 mutation carriers, identified predominantly by multigene panel testing, and their 649 family members were reviewed. The percentage of subjects fulfilling the IGCLC 2015 and 2020 criteria was calculated, once without making any assumptions about unavailable pathology, and once assuming gastric cancer to be diffuse when pathology was unavailable. For comparison, we calculated the percentage of subjects who fulfilled our proposed criteria.

Results When making no assumptions about missing pathology, a small (19%) and equal percentage of CDH1 mutation carriers fulfilled the IGCLC 2015 and 2020 criteria. When assuming unspecified gastric cancer to be diffuse, 45 out of 112 (40%) subjects met the 2015 criteria and 53 out of 112 (47%) met the 2020 criteria. Eighty-seven per cent (97/112) fulfilled our proposed criteria.

Conclusion In consecutive cases, mostly unselected for clinical criteria of HDGC, the IGCLC 2020 criteria are, at best, marginally more sensitive than previous iterations, but they are also more cumbersome. Unavailable cancer pathology reports are a real-world obstacle to their proper application. Our proposed Yale criteria both address this issue and offer significantly greater sensitivity than the IGCLC 2020 criteria.

  • genetic carrier screening
  • genetic predisposition to disease
  • genetics
  • medical
  • gastrointestinal diseases

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

View Full Text


  • Twitter @Dr_NJRodriguez, @rachidkaram

  • Contributors BAL, RMX and XL designed and supervised the overall project. BAL, RMX, NJR and RK compiled and analysed the data and performed the statistical analysis. BAL, RMX and XL interpreted the data and drafted the manuscript. They take full responsibility for the integrity of the data and the accuracy of the data analysis. RK critically revised the manuscript for important intellectual content. XL is the guarantor of this study.

  • Funding This work was supported by the National Institutes of Health (T32 DK007017 to BAL) and internal funds from the Yale Cancer Center (XL).

  • Disclaimer The study sponsors had no role in the design of the study; in the collection, analysis, or interpretation of the data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.