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A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report

Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic varian...

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Autores principales: Walker, Romy, Clendenning, Mark, Joo, Jihoon E., Xue, Jessie, Mahmood, Khalid, Georgeson, Peter, Como, Julia, Joseland, Sharelle, Preston, Susan G., Chan, James M., Jenkins, Mark A., Rosty, Christophe, Macrae, Finlay A., Di Palma, Stephanie, Campbell, Ainsley, Winship, Ingrid M., Buchanan, Daniel D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541337/
https://www.ncbi.nlm.nih.gov/pubmed/37318702
http://dx.doi.org/10.1007/s10689-023-00337-0
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author Walker, Romy
Clendenning, Mark
Joo, Jihoon E.
Xue, Jessie
Mahmood, Khalid
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Chan, James M.
Jenkins, Mark A.
Rosty, Christophe
Macrae, Finlay A.
Di Palma, Stephanie
Campbell, Ainsley
Winship, Ingrid M.
Buchanan, Daniel D.
author_facet Walker, Romy
Clendenning, Mark
Joo, Jihoon E.
Xue, Jessie
Mahmood, Khalid
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Chan, James M.
Jenkins, Mark A.
Rosty, Christophe
Macrae, Finlay A.
Di Palma, Stephanie
Campbell, Ainsley
Winship, Ingrid M.
Buchanan, Daniel D.
author_sort Walker, Romy
collection PubMed
description Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.
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spelling pubmed-105413372023-10-01 A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report Walker, Romy Clendenning, Mark Joo, Jihoon E. Xue, Jessie Mahmood, Khalid Georgeson, Peter Como, Julia Joseland, Sharelle Preston, Susan G. Chan, James M. Jenkins, Mark A. Rosty, Christophe Macrae, Finlay A. Di Palma, Stephanie Campbell, Ainsley Winship, Ingrid M. Buchanan, Daniel D. Fam Cancer Brief Report Germline pathogenic variants in the DNA mismatch repair (MMR) genes (Lynch syndrome) predispose to colorectal (CRC) and endometrial (EC) cancer. However, mosaic variants in the MMR genes have been rarely described. We identified a likely de novo mosaic MSH6:c.1135_1139del p.Arg379* pathogenic variant in a patient diagnosed with suspected Lynch syndrome/Lynch-like syndrome. The patient developed MSH6-deficient EC and CRC at 54 and 58 years of age, respectively, without a detectable germline MMR pathogenic variant. Multigene panel sequencing of tumor and blood-derived DNA identified an MSH6 somatic mutation (MSH6:c.1135_1139del p.Arg379*) common to both the EC and CRC, raising suspicion of mosaicism. A droplet digital polymerase chain reaction (ddPCR) assay detected the MSH6 variant at 5.34% frequency in normal colonic tissue, 3.49% in saliva and 1.64% in blood DNA, demonstrating the presence of the MSH6 variant in all three germ layers. This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling. Springer Netherlands 2023-06-15 2023 /pmc/articles/PMC10541337/ /pubmed/37318702 http://dx.doi.org/10.1007/s10689-023-00337-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Brief Report
Walker, Romy
Clendenning, Mark
Joo, Jihoon E.
Xue, Jessie
Mahmood, Khalid
Georgeson, Peter
Como, Julia
Joseland, Sharelle
Preston, Susan G.
Chan, James M.
Jenkins, Mark A.
Rosty, Christophe
Macrae, Finlay A.
Di Palma, Stephanie
Campbell, Ainsley
Winship, Ingrid M.
Buchanan, Daniel D.
A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title_full A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title_fullStr A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title_full_unstemmed A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title_short A mosaic pathogenic variant in MSH6 causes MSH6-deficient colorectal and endometrial cancer in a patient classified as suspected Lynch syndrome: a case report
title_sort mosaic pathogenic variant in msh6 causes msh6-deficient colorectal and endometrial cancer in a patient classified as suspected lynch syndrome: a case report
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541337/
https://www.ncbi.nlm.nih.gov/pubmed/37318702
http://dx.doi.org/10.1007/s10689-023-00337-0
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