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Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants
Author(s) -
Lee Kristy,
Krempely Kate,
Roberts Maegan E.,
Anderson Michael J.,
Carneiro Fatima,
Chao Elizabeth,
Dixon Katherine,
Figueiredo Joana,
Ghosh Rajarshi,
Huntsman David,
Kaurah Pardeep,
Kesserwan Chimene,
Landrith Tyler,
Li Shuwei,
Mensenkamp Arjen R.,
Oliveira Carla,
Pardo Carolina,
Pesaran Tina,
Richardson Matthew,
Slavin Thomas P.,
Spurdle Amanda B.,
Trapp Mackenzie,
Witkowski Leora,
Yi Charles S.,
Zhang Liying,
Plon Sharon E.,
Schrader Kasmintan A.,
Karam Rachid
Publication year - 2018
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23650
Subject(s) - medical genetics , germline , biology , genomics , genetics , molecular pathology , computational biology , bioinformatics , gene , genome
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.