Optimising Clinical Care Through CDH1-Specific Germline Variant Curation: Improvement of Clinical Assertions and Updated Curation Guidelines

Authors

Xi Luo
Jamie L Maciaszek
Bryony A Thompson
Huei San Leong
Katherine Dixon
Sónia Sousa
Michael Anderson
Maegan E Roberts
Kristy Lee
Amanda B Spurdle
Arjen R Mensenkamp
Terra Brannan
Carolina Pardo
Liying Zhang
Tina Pesaran
Sainan Wei
Grace-Ann Fasaye
Chimene Kesserwan
Brian H Shirts
Jeremy L Davis
Carla Oliveira
Sharon E Plon
Kasmintan A Schrader
Rachid Karam
ClinGen CDH1 Variant Curation Expert Panel

Publication Date

6-1-2023

Journal

Journal of Medical Genetics

DOI

10.1136/jmg-2022-108807

PMID

36600593

PMCID

PMC10202836

PubMedCentral® Posted Date

6-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Genetic Variation, Genetic Testing, Germ-Line Mutation, Stomach Neoplasms, Germ Cells, Antigens, CD, Cadherins

Abstract

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 The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.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.