Article Text
Abstract
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 The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.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 (https://www.ncbi.nlm.nih.gov/clinvar/submitters/506817/) and all evidence codes used in variant classifications are available in the ClinGen Evidence Repository (https://erepo.clinicalgenome.org/evrepo/).
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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 (https://www.ncbi.nlm.nih.gov/clinvar/submitters/506817/) and all evidence codes used in variant classifications are available in the ClinGen Evidence Repository (https://erepo.clinicalgenome.org/evrepo/).
Footnotes
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.
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