Constitutional Mismatch Repair Deficiency Mimicking Lynch Syndrome is Associated with Hypomorphic Mismatch Repair Gene Variants

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2024 May 24

PMID 38789506

Authors

Richard Gallon

Carlijn Brekelmans

Marie Martin

Vincent Bours

Esther Schamschula

Albert Amberger

Martine Muleris

Chrystelle Colas

Jeroen Dekervel

Gert De Hertogh

Jerome Coupier

Orphal Colleye

Edith Sepulchre

John Burn

Hilde Brems

Eric Legius

Katharina Wimmer

Affiliations

Soon will be listed here.

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.

Citing Articles

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