Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants. Gallon, R., Brekelmans, C., Martin, M., Bours, V., Schamschula, E., Amberger, A., Muleris, M., Colas, C., Dekervel, J., De Hertogh, G., Coupier, J., Colleye, O., Sepulchre, E., Burn, J., Brems, H., Legius, E., & Wimmer, K. npj Precision Oncology, 8(1):1–11, May, 2024. Publisher: Nature Publishing Group![Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex 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\textgreaterT (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G\textgreaterA (p.(Glu102=)). MLH1 c.306G\textgreaterA 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.
@article{gallon_constitutional_2024,
title = {Constitutional mismatch repair deficiency mimicking {Lynch} syndrome is associated with hypomorphic mismatch repair gene variants},
volume = {8},
copyright = {2024 The Author(s)},
issn = {2397-768X},
url = {https://www.nature.com/articles/s41698-024-00603-z},
doi = {10.1038/s41698-024-00603-z},
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{\textgreater}T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G{\textgreater}A (p.(Glu102=)). MLH1 c.306G{\textgreater}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.},
language = {en},
number = {1},
urldate = {2024-05-28},
journal = {npj Precision Oncology},
author = {Gallon, Richard and Brekelmans, Carlijn and Martin, Marie and Bours, Vincent and Schamschula, Esther and Amberger, Albert and Muleris, Martine and Colas, Chrystelle and Dekervel, Jeroen and De Hertogh, Gert and Coupier, Jérôme and Colleye, Orphal and Sepulchre, Edith and Burn, John and Brems, Hilde and Legius, Eric and Wimmer, Katharina},
month = may,
year = {2024},
note = {Publisher: Nature Publishing Group},
keywords = {Alamut, Alamut Visual Plus, Alamut Visual Plus v.1.7.2, Cancer genetics, Diagnosis},
pages = {1--11},
}
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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\\textgreaterT (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G\\textgreaterA (p.(Glu102=)). MLH1 c.306G\\textgreaterA 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. 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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{\\textgreater}T (p.(Arg1076Cys)), or variant of uncertain significance (VUS), MLH1 c.306G{\\textgreater}A (p.(Glu102=)). MLH1 c.306G{\\textgreater}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. 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