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BackgroundGermline pathogenic variants inCDH1are 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 germlineCDH1variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen)CDH1Variant Curation Expert Panel (VCEP) developed specifications forCDH1variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.MethodsCDH1variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoingCDH1variant curations. TheCDH1VCEP reviewed 273 variants using updatedCDH1specifications and incorporated published and unpublished data provided by diagnostic laboratories.ResultsUpdatedCDH1-specific interpretation guidelines include 11 major modifications since the initial specifications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.ConclusionsThe development and evolution ofCDH1-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.

Supplementary Material PDF file - 709K, Supplementary Tables 1 and 2, supplementary methods, supplementary figure legends and supplementary figures

Supplementary Tables S3-S4 XLSX file - 576K, Gene set analysis (Camera) and differentially expressed genes

BACKGROUND: Germline pathogenic variants in CDH1 are associated with increased risk for 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 upon 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 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. To date, the only missense variants classified as pathogenic or likely pathogenic are known to affect splicing and therefore, functional studies are not validated for use in the interpretation of CDH1 variants. CONCLUSIONS: The 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 which ultimately leads to more effective clinical management recommendations.

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.