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

Richard Gallon; Carlijn Brekelmans; Marie Martin; Vincent Bours; Esther Schamschula; Albert Amberger; Martine Muleris; Chrystelle Colas; Jeroen Dekervel; Gert De Hertogh; Jérôme Coupier; Orphal Colleye; Edith Sepulchre; John Burn; Hilde Brems; Eric Legius; Katharina Wimmer

doi:10.1038/s41698-024-00603-z

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

NPJ Precis Oncol. 2024 May 24;8(1):119. doi: 10.1038/s41698-024-00603-z.

Authors

Richard Gallon¹, Carlijn Brekelmans², Marie Martin³, Vincent Bours³, Esther Schamschula⁴, Albert Amberger⁴, Martine Muleris^{5

6}, Chrystelle Colas^{7

8}, Jeroen Dekervel⁹, Gert De Hertogh¹⁰, Jérôme Coupier¹¹, Orphal Colleye¹², Edith Sepulchre³, John Burn¹³, Hilde Brems², Eric Legius², Katharina Wimmer¹⁴

Affiliations

¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. richard.gallon@newcastle.ac.uk.
² Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium.
³ CHU, University of Liège, Liège, Belgium.
⁴ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
⁵ Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
⁶ Inserm UMRS_938, Sorbonne Université, Centre de Recherche Saint Antoine, Paris, France.
⁷ Département de Génétique, Institut Curie, Paris, France.
⁸ INSERM U830, Université de Paris, Paris, France.
⁹ Department of Digestive Oncology, University Hospital Leuven, Leuven, Belgium.
¹⁰ Department of Pathology, University Hospital Leuven, Leuven, Belgium.
¹¹ Human Genetics, CHU Liège, Liège, Belgium.
¹² Department of Pathology, CHU Liège, Liège, Belgium.
¹³ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹⁴ Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria. katharina.wimmer@i-med.ac.at.

Abstract

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.

Grants and funding

C569/A24991/Cancer Research UK (CRUK)