ClinGen CDH1 specifications for the ACMG/AMP guidelines: improvement of germline variant clinical assertions and updated curation guidelines

AbstractPurposeThe 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 for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar.ResultsUpdated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications.ConclusionThe development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.