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Original research
Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines
  1. Xi Luo1,
  2. Jamie L Maciaszek2,
  3. Bryony A Thompson3,
  4. Huei San Leong4,
  5. Katherine Dixon5,
  6. Sónia Sousa6,7,
  7. Michael Anderson8,
  8. Maegan E Roberts9,
  9. Kristy Lee10,
  10. Amanda B Spurdle11,
  11. Arjen R Mensenkamp12,
  12. Terra Brannan13,
  13. Carolina Pardo8,
  14. Liying Zhang14,
  15. Tina Pesaran13,
  16. Sainan Wei15,
  17. Grace-Ann Fasaye16,
  18. Chimene Kesserwan17,
  19. Brian H Shirts18,
  20. Jeremy L Davis19,
  21. Carla Oliveira6,7,20,
  22. Sharon E Plon1,
  23. Kasmintan A Schrader5,21,
  24. Rachid Karam13
  25. on behalf of the ClinGen CDH1 Variant Curation Expert Panel
    1. 1 Department of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Houston, Texas, USA
    2. 2 Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA
    3. 3 Department of Pathology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
    4. 4 Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
    5. 5 Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada
    6. 6 Instituto de Investigação e Inovação em Saúde – (i3S), University of Porto, Porto, Portugal
    7. 7 Institute of Molecular Pathology and Immunology - (IPATIMUP), University of Porto, Porto, Portugal
    8. 8 Invitae Corporation, San Francisco, California, USA
    9. 9 The Ohio State University, Columbus, Ohio, USA
    10. 10 Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    11. 11 Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
    12. 12 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
    13. 13 Ambry Genetics, Aliso Viejo, California, USA
    14. 14 Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, USA
    15. 15 Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky, USA
    16. 16 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
    17. 17 National Institutes of Health, Bethesda, Maryland, USA
    18. 18 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
    19. 19 Surgical Oncology Program, National Cancer Institute, Bethesda, Maryland, USA
    20. 20 Department of Pathology, University of Porto, Porto, Portugal
    21. 21 Hereditary Cancer Program, BC Cancer, Vancouver, British Columbia, Canada
    1. Correspondence to Dr Rachid Karam, Ambry Genetics Corp, Aliso Viejo, California, USA; rkaram{at}


    Background Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.

    Methods CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.

    Results Updated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.

    Conclusions The development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.

    • Genetic Predisposition to Disease
    • Gastrointestinal Diseases
    • Genetics, Medical
    • Genetic Variation

    Data availability statement

    Data are available in a public, open access repository. All variants have been submitted to ClinVar by the CDH1 VCEP ( and all evidence codes used in variant classifications are available in the ClinGen Evidence Repository (

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    Data availability statement

    Data are available in a public, open access repository. All variants have been submitted to ClinVar by the CDH1 VCEP ( and all evidence codes used in variant classifications are available in the ClinGen Evidence Repository (

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    • Twitter @JeremyLDavisMD, @rachidkaram

    • XL and JLM contributed equally.

    • Collaborators The ClinGen CDH1 VCEP members include coauthors (RK and KS as co-chairs; XL, JM, BAT, HSL, KD, SS, MA, MR, KL, ABS, AM, TB, CP, LZ, TP, SW, G-AF, CK, BS, JLD, CO and SP) and others as follows: Pardeep Kaurah (BC Cancer Research Centre, Canada), Fatima Carneiro (University of Porto, Portugal), Elizabeth Chao (University of California Irvine, USA), Giovanni Corso (University of Milano, Italy), Joana Figueiredo (University of Porto, Portugal), David Huntsman (University of British Columbia, Canada), Sean Tavtigian (University of Utah, USA) and Chella van der Post (Radboud University Medical Center, The Netherlands).

    • Contributors Conceptualisation: XL, JM, KS, RK. Data curation: XL, JM, BAT, HSL, KD, SS, SW. Formal analysis: XL, JM, ABS. Funding acquisition: XL, SP. Writing—original draft: XL, JM. Writing—review and editing: XL, JM, BAT, HSL, KD, SS, MA, MR, KL, ABS, AM, TB, CP, LZ, TP, G-AF, CK, BS, JLD, CO, SP, KS, RK. All authors were members of the ClinGen CDH1 Variant Curation Expert Panel. Guarantor: RK.

    • Funding The NIH National Human Genome Research Institute supported this work through U41HG009649 (XL and SP). ABS was supported by an Australian NHMRC Investigator Fellowship (APP177524).

    • Competing interests MA, MR, AM, TB, CP, TP, CO, SP and RK are an employee, a trainee or a consultant for a commercial laboratory that offers genetic testing for CDH1. LZ reports that family members hold leadership positions and ownership interests in Decipher Medicine.

    • 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.