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Lookup NU author(s): Dr Richard Gallon, Professor Sir John BurnORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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
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