Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline <i>CDH1</i> sequence variants

TLDR

The 2015 ACMG/AMP variant curation guidelines provide a general framework for assessing pathogenicity but are not gene specific, and germline pathogenic CDH1 variants underlie hereditary diffuse gastric cancer and lobular breast cancer, a syndrome that requires multidisciplinary management. ClinGen’s Hereditary Cancer Domain established a CDH1 variant curation expert panel to develop and implement CDH1‑specific rules for variant classification. The panel’s CDH1 specifications were derived and validated through a systematic evaluation of ∼827,000 CDH1 alleles from clinical laboratory data. Applying the CDH1‑specific guidelines reduced variants of uncertain significance and resolved conflicting ClinVar assertions, and the panel recommends their use for assessing variants in this clinically actionable gene.

Abstract

The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.