Extent of investigation and management of cases of ‘unexplained’ mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus

Sep 21, 2026

Uploaded by Maeve

Mismatch repair deficiency (dMMR) is a key cancer feature linked to Lynch syndrome, yet most dMMR cases arise from sporadic somatic events rather than inherited genetics. “Lynch-like syndrome” has been used to support colorectal surveillance when somatic and germline testing is uninformative, but dMMR is now identified across many tumour types where hereditary suspicion is low. This work established current UK practices and developed national guidance for investigating and managing relatives of patients with unexplained dMMR. A virtual multidisciplinary consensus meeting used premeeting surveys, structured discussion, and in-meeting polling to define best-practice recommendations.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages9

Reading Time23 min

AccessFree to download

Background

dMMR and unexplained cases

Methods

Virtual consensus process

Results

Variability in testing access and guidance factors

Conclusion

Risk management tailored to suspicion and resources

Cancer genetics Original research Extent of investigation and management of cases of‘unexplained’ mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus Terri Patricia McVeigh , 1,2 Kevin J Monahan,3,4 Joseph Christopher,5,6 Nick West,7,8 Malcolm Scott,9 Jennie Murray, 10 Helen Hanson , 11,12 UKCGG dMMR Consensus Meeting Attendees ► 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-2024-109886](10.1136/jmg-2024-109886)) . For numbered affiliations see end of article. Correspondence to Dr Terri Patricia McVeigh, Cancer Genetics Unit, Royal Marsden Hospital NHS Trust, London SW3 6JJ, UK; [terri.mcveigh@nhs.net](terri.mcveigh@nhs.net)[ ](terri.mcveigh@nhs.net)Dr Helen Hanson; [h.hanson@exeter.ac.uk](h.hanson@exeter.ac.uk) Received 17 January 2024 Accepted 9 March 2024 Published Online First 26 March 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. To cite: McVeigh TP, Monahan KJ, Christopher J, et al. J Med Genet 2024;61:707–715 . ABSTRACT Background Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term ’Lynch-like syndrome’(LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practicesand develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. Methods This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussionsand in-meeting polling to formulate best practice guidance. Results We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term ’unexplained dMMR’ was recommended over LLS. Conclusion Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigationsin low-suspicion families. INTRODUCTION Lynch syndrome is defined by the identification of constitutional pathogenic variants in four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2). Although functional MMR deficiency (dMMR) is a hallmark of cancers associated with Lynch syndrome, dMMR may also be a feature of | WHAT IS ALREADY KNOWN ON THIS TOPIC | | --- | | ⇒ Mismatch repair deficiency (dMMR) may be due to an underlying heritable variant impacting mismatch repair gene function or may be due to a sporadic, somatic aetiology. Even in cases where germline and somatic testing is undertaken, dMMR in a minority of cases remains unexplained. The investigative pathway and clinical management of patients with tumours demonstrating unexplained dMMR, and their relatives, pose challenges.
WHAT THIS STUDY ADDS | | ⇒ Following a national, multidisciplinary consensus meeting, we have outlined a pragmatic approach t

FAQs

What does the document aim to address about unexplained dMMR?

It develops current-practice understanding and national guidance for investigating and managing relatives of patients whose cancers show unexplained dMMR when hereditary causes are unclear.

How was the consensus guidance created?

Through a virtual consensus meeting with UK stakeholders, supported by premeeting surveys, structured discussions, and in-meeting polling to formulate best-practice recommendations.

Why is “unexplained dMMR” emphasized over “Lynch-like syndrome”?

The study recommends using the term “unexplained dMMR” rather than “Lynch-like syndrome,” reflecting the need for a pragmatic approach when somatic and germline testing cannot clarify hereditary aetiology.

Sep 21, 2026

Uploaded by Maeve