[en] 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.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
Gallon, Richard ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK. richard.gallon@newcastle.ac.uk
Brekelmans, Carlijn; Centre for Human Genetics, University Hospital Leuven, Leuven, Belgium
Martin, Marie ; Université de Liège - ULiège > Département des sciences cliniques
Bours, Vincent ; Université de Liège - ULiège > GIGA > GIGA Cancer - Human Genetics
Schamschula, Esther ; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Amberger, Albert; Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
Muleris, Martine; Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France ; Inserm UMRS_938, Sorbonne Université, Centre de Recherche Saint Antoine, Paris, France
Colas, Chrystelle; Département de Génétique, Institut Curie, Paris, France ; INSERM U830, Université de Paris, Paris, France
Dekervel, Jeroen; Department of Digestive Oncology, University Hospital Leuven, Leuven, Belgium
De Hertogh, Gert; Department of Pathology, University Hospital Leuven, Leuven, Belgium
COUPIER, Jérôme ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Colleye, Orphal ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
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