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|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.||Austin Authors:||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||Affiliation:||Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne
University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Melbourne Bioinformatics, The University of Melbourne, Melbourne, Parkville, VIC, 3010, Australia.
Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.;Department of Medicine, The University of Melbourne, Melbourne, VIC, 3000, Australia.
University of Queensland, Brisbane, QLD, 4072, Australia.
Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC, 3010, Australia.
Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia
Genomic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, 3000, Australia
Department of Medicine, The University of Melbourne, Melbourne, VIC, 3000, Australia.
Genomic Medicine and Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.
|Issue Date:||Oct-2023||Date:||2023||Publication information:||Familial Cancer 2023-10; 22(4)||Abstract:||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.||URI:||https://ahro.austin.org.au/austinjspui/handle/1/33122||DOI:||10.1007/s10689-023-00337-0||ORCID:||Journal:||Familial Cancer||PubMed URL:||37318702||ISSN:||1573-7292||Type:||Journal Article||Subjects:||DNA mismatch repair
Droplet digital PCR
Suspected Lynch syndrome
Targeted tumor sequencing
|Appears in Collections:||Journal articles|
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checked on Dec 6, 2023
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