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Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants

Lookup NU author(s): Dr Richard Gallon, Professor Sir John BurnORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2024. Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are distinct cancer syndromes caused, respectively, by mono- and bi-allelic germline mismatch repair (MMR) variants. LS predisposes to mainly gastrointestinal and genitourinary cancers in adulthood. CMMRD predisposes to brain, haematological, and LS-spectrum cancers from childhood. Two suspected LS patients with first cancer diagnosis aged 27 or 38 years were found to be homozygous for an MMR (likely) pathogenic variant, MSH6 c.3226C>T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G>A (p.(Glu102=)). MLH1 c.306G>A was shown to cause leaky exon 3 skipping. The apparent genotype-phenotype conflict was resolved by detection of constitutional microsatellite instability in both patients, a hallmark feature of CMMRD. A hypomorphic effect of these and other variants found in additional late onset CMMRD cases, identified by literature review, likely explains a LS-like phenotype. CMMRD testing in carriers of compound heterozygous or homozygous MMR VUS may find similar cases and novel hypomorphic variants. Individualised management of mono- and bi-allelic carriers of hypomorphic MMR variants is needed until we better characterise the associated phenotypes.


Publication metadata

Author(s): Gallon R, Brekelmans C, Martin M, Bours V, Schamschula E, Amberger A, Muleris M, Colas C, Dekervel J, De Hertogh G, Coupier J, Colleye O, Sepulchre E, Burn J, Brems H, Legius E, Wimmer K

Publication type: Article

Publication status: Published

Journal: npj Precision Oncology

Year: 2024

Volume: 8

Online publication date: 24/05/2024

Acceptance date: 08/05/2024

Date deposited: 13/06/2024

ISSN (electronic): 2397-768X

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41698-024-00603-z

DOI: 10.1038/s41698-024-00603-z

Data Access Statement: For access to the study data, please contact the corresponding authors Dr Richard Gallon (richard.gallon@newcastle.ac.uk) and Associate Professor Katharina Wimmer (katharina.wimmer@i-med.ac.at).


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Funding

Funder referenceFunder name
C569/A24991
Cancer Research UK
Aspirin for Cancer Prevention (AsCaP) collaboration
European Union, ERN-2016—Framework Partnership Agreement 2017–2021

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