Portal de investigação
Optimising clinical care through CDH1-specific germline variant curation: improvement of clinical assertions and updated curation guidelines
Data de publicação:
Data Ahead of Print:
Autores da FMUP
Participantes de fora da FMUP
- Luo, Xi
- Maciaszek, Jamie L.
- Thompson, Bryony A.
- San Leong, Huei
- Dixon, Katherine
- Sousa, Sonia
- Anderson, Michael
- Roberts, Maegan E.
- Lee, Kristy
- Spurdle, Amanda B.
- Mensenkamp, Arjen R.
- Brannan, Terra
- Pardo, Carolina
- Zhang, Liying
- Pesaran, Tina
- Wei, Sainan
- Fasaye, Grace-Ann
- Kesserwan, Chimene
- Shirts, Brian H.
- Davis, Jeremy L.
- Plon, Sharon E.
- Schrader, Kasmintan A.
- Karam, Rachid
- ClinGen CDH1 Variant Curation Expe
Abstract
BackgroundGermline pathogenic variants in CDH1 are 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 germline CDH1 variants critical for physicians deciding on 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. 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. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories. ResultsUpdated CDH1-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 of CDH1-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.
Dados da publicação
- ISSN/ISSNe:
- 0022-2593, 1468-6244
- Tipo:
- Article
- Páginas:
- 568-575
Journal of Medical Genetics BMJ Publishing Group
Citações Recebidas na Web of Science: 12
Documentos
- Não há documentos
Filiações
Keywords
- Genetic Predisposition to Disease; Gastrointestinal Diseases; Genetics; Medical; Genetic Variation
Campos de estudo
Proyectos asociados
E-cadherin and CD44v6 in Gastric Cancer: Role, crosstalk and clinical implications
Investigador Principal: Carla Isabel Gonçalves de Oliveira
Estudo Clínico Académico . 2021
Citar a publicação
Luo XI,Maciaszek JL,Thompson BA,San Leong H,Dixon K,Sousa S,Anderson M,Roberts ME,Lee K,Spurdle AB,Mensenkamp AR,Brannan T,Pardo C,Zhang L,Pesaran T,Wei S,Fasaye G,Kesserwan C,Shirts BH,Davis JL,Oliveira C,Plon SE,Schrader KA,Karam R,ClinGen Variant Curation Expe CDH1. Optimising clinical care through <i>CDH1</i>-specific germline variant curation: improvement of clinical assertions and updated curation guidelines. J. Med. Genet. 2023. 60. (6):p. 568-575. IF:4,000. (2).
