1. Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.
- Author
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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, and Wimmer, Katharina
- Subjects
HEREDITARY nonpolyposis colorectal cancer ,GENETIC variation ,LITERATURE reviews ,GASTROINTESTINAL cancer ,DNA mismatch repair ,CANCER patients ,CHILDHOOD cancer - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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