Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data - Abstract - Results and conclusion

Q: What question does the study address about ATM and CHEK2 variants?

It evaluates whether coding variants in ATM and CHEK2 are associated with cancer risk across all cancer types, beyond the previously established link to breast cancer.

Q: How were cancer associations for ATM and CHEK2 assessed in this research?

Associations were tested using UK Biobank whole-exome sequence data linked to cancer registration, analyzed as both a retrospective case-control and a prospective cohort study.

Q: What were the main findings for protein-truncating variants and rare missense variants?

ATM protein-truncating variants showed increased risks across multiple cancers, and CHEK2 protein-truncating variants were linked to several cancers; rare missense variant carriers also exhibited increased risks for specific cancer types.

Sep 21, 2026

Uploaded by River Wang

Deleterious germline variants in ATM and CHEK2 have been linked to moderately increased breast cancer risk, while risks for other cancers remain insufficiently defined. Whole-exome sequence data from UK Biobank linked to cancer registry records (348,488 participants) were analyzed using retrospective case-control and prospective cohort designs. Coding variant associations were estimated by cancer type and gene, separating protein-truncating and rare missense variants, and reporting odds ratios, hazard ratios, and combined relative risks.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages7

Reading Time18 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusion

Introduction

Cancer susceptibility gene panel testing

Study focus on ATM and CHEK2 variants

What this study adds

Relative and absolute risk assessment across cancer types

Significance for ATM and CHEK2 protein-truncating variants

Significance for rare missense variants

How this study might affect research, practice, or policy

Cancer genetics Original research Protein-truncating and rare missense variants in ATM and CHEK2 and associations with cancer in UK Biobank whole-exome sequence data Toqir K Mukhtar , 1,2 Naomi Wilcox, 1 Joe Dennis, 1 Xin Yang , 1 Marc Naven, 1 Nasim Mavaddat, 1 John R B Perry,3 Eugene Gardner,4 Douglas F Easton 1,5 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1136/jmg-2024-110127](10.1136/jmg-2024-110127)) . 1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK 2Department of Primary Care and Public Health, Imperial College London, London, UK 3MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK 4Metabolic Research Laboratory, Institute of Metabolic Science, University of Cambridge, Cambridge, UK 5Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK Correspondence to Toqir K Mukhtar, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; [tm621@medschl.cam.ac.uk](tm621@medschl.cam.ac.uk) Received 14 June 2024 Accepted 18 August 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. To cite: Mukhtar TK, Wilcox N, Dennis J, et al. J Med Genet Epub ahead of print: [please include Day Month Year] . doi:10 . 1136/ jmg-2024-110127 ABSTRACT Background Deleterious germline variants in ATM and CHEK2 have been associated with a moderately increased risk of breast cancer. Risks for other cancers remain unclear. Methods Cancer associations for coding variants in ATM and CHEK2 were evaluated using whole-exome sequence data from UK Biobank linked to cancer registration data (348 488 participants), and analysed both as a retrospective case-control and a prospective cohort study. Odds ratios, hazard ratios, and combined relative risks (RRs) were estimated by cancer type and gene. Separate analyses were performed for proteintruncating variants (PTVs) and rare missense variants (rMSVs; allele frequency <0 . 1%) . Results PTVs in ATM were associated with increased risks of nine cancers at p<0 .001 (pancreas, oesophagus, lung, melanoma, breast, ovary, prostate, bladder, lymphoid leukaemia (LL)), and three at p<0.05 (colon, diffuse non-Hodgkin’s lymphoma (DNHL), rectosigmoid junction) . Carriers of rMSVs had increased risks of four cancers (p<0 .05: stomach, pancreas, prostate, Hodgkin’s disease (HD)) . RRs were highest for breast, prostate, and any cancer where rMSVs lay in the FAT or PIK domains, and had a Combined Annotation Dependent Depletion score in the highest quintile. PTVs in CHEK2 were associated with three cancersat p<0 .001 (breast, prostate, HD) and six at p<0 .05 (oesophagus, melanoma, ovary, kidney, DNHL, myeloid leukaemia) . Carriers of rMSVs had increased risks of five cancers (p<0 .001: breast, prostate, LL; p<0 .05: melanoma, multiple myeloma) . Conclusion PTVs in ATM and CHEK2 are associated with a wide range of cancers, with the highest RR for pancreatic cancer in ATM PTV carriers. These findings can inform genetic counselling of carriers. INTRODUCTION Gene panel testing for cancer susceptibility is now an important part of clinical practice. To provide reliable genetic counselling, it is important to be able to provide risks for all cancer types. Many susceptibility genes, notably BRCA1, BRCA2, and themismatch repair genes, are associated with multiple types of cancer,1 2 but in general, cancer pleiotropy is poorly understood. Here we consider rare variants in two genes, Checkpoint Kinase 2 (CHEK2) and Ataxia-Telangiectasia Mutated (ATM), that are included on many cancer gene panels. Variants in | WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ While previous research shows there is evidenc

FAQs

What question does the study address about ATM and CHEK2 variants?

It evaluates whether coding variants in ATM and CHEK2 are associated with cancer risk across all cancer types, beyond the previously established link to breast cancer.

How were cancer associations for ATM and CHEK2 assessed in this research?

Associations were tested using UK Biobank whole-exome sequence data linked to cancer registration, analyzed as both a retrospective case-control and a prospective cohort study.

What were the main findings for protein-truncating variants and rare missense variants?

ATM protein-truncating variants showed increased risks across multiple cancers, and CHEK2 protein-truncating variants were linked to several cancers; rare missense variant carriers also exhibited increased risks for specific cancer types.

Sep 21, 2026

Uploaded by River Wang