The gene-disease relationship for CHEK2 remains listed as ‘Li-Fraumeni syndrome 2’ in public resources such as OMIM and MONDO, despite published evidence to the contrary, causing frustration among Li-Fraumeni syndrome (LFS) clinical experts. Here, we compared personal cancer characteristics of 2095 CHEK2 and 248 TP53 pathogenic variant carriers undergoing multigene panel testing at Ambry Genetics against 15 135 individuals with no known pathogenic variant. Our results from a within-cohort logistic regression approach highlight obvious differences between clinical presentation of TP53 and CHEK2 pathogenic variant carriers, with no evidence of CHEK2 being associated with any of the TP53-related core LFS cancers. These findings emphasise the need to replace ‘Li-Fraumeni syndrome 2’ as the CHEK2-associated disease name, thereby limiting potential confusion.
- Genetic Variation
- Germline Mutation
- Human Genetics
- Genetic Predisposition to Disease
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Contributors CF: Conceptualisation, analysis and interpretation of data, writing—original draft. MR: Planning, acquisition of data, writing—review and editing. TP: Planning, acquisition of data, writing—review and editing. AY: Acquisition of data, data curation. CH: Acquisition of data, data curation. PJ: Interpretation of data, writing—review and editing. ABS: Conceptualisation, interpretation of data, writing—original draft.
Funding ABS was supported by an NHMRC Investigator Fellowship (APP177524). CF was supported in part by NHMRC project funding (APP1161589), and a grant from the National Breast Cancer Foundation, Australia (IIRS-21-102). For the purposes of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Competing interests MR, TP, AY and CH are paid employees of Ambry Genetics.
Provenance and peer review Not commissioned; externally peer reviewed.