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- Title
Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.
- Authors
Gallon, Richard; Brekelmans, Carlijn; Martin, Marie; Bours, Vincent; Schamschula, Esther; Amberger, Albert; Muleris, Martine; Colas, Chrystelle; Dekervel, Jeroen; De Hertogh, Gert; Coupier, Jérôme; Colleye, Orphal; Sepulchre, Edith; Burn, John; Brems, Hilde; Legius, Eric; Wimmer, Katharina
- 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.
- Subjects
HEREDITARY nonpolyposis colorectal cancer; GENETIC variation; LITERATURE reviews; GASTROINTESTINAL cancer; DNA mismatch repair; CANCER patients; CHILDHOOD cancer
- Publication
NPJ Precision Oncology, 2024, Vol 8, Issue 1, p1
- ISSN
2397-768X
- Publication type
Article
- DOI
10.1038/s41698-024-00603-z