Inversions within the MSH2 gene

Anna C Ritchie1, Shannon Cowie1, Desirée du Sart1.

1Molecular Genetics Laboratory, VCGS Pathology, Murdoch Childrens Research Institute, Flemington Rd, Parkville, Victoria 3052.

Lynch syndrome is caused by a germline mutation in a mismatch repair gene (MLH1, MSH2, MSH6, PMS2 and EPCAM) resulting in a predisposition to colorectal and other cancers.  Testing of these MMR genes by Next Generation sequencing and MLPA analysis will identify point mutations, small deletions and insertions, splice site mutations as well as intragenic and whole gene deletions and duplications. However, gene rearrangements, such as inversions and chromosome translocations, will not be detected.

A 10Mb inversion within the MSH2 gene was initially identified by Wagner et al. 2002 and a further study by Rhees et al. 2014 found that six out ten previously unexplained MSH2-type Lynch syndrome families had this inversion.  To assist in identifying these mutations, recently two new probes have been introduced into the MCR-Holland P003-D1 MLPA kit to detect this recurrent pathogenic inversion.  The assay focuses on the breakpoint within intron 7 of the MSH2 gene which will bind and produce a peak at 265 and 317nt when the inversion is present.  We have confirmed the same 10Mb inversion by PCR amplification and gel electrophoresis in a family where this inversion was previously identified.  We have also identified another inversion of exons 2 to 6 within the MSH2 gene in a different family with a history of Lynch syndrome, which will not be detected by the MLPA assay.  It is currently unclear how common inversions within the MSH2 gene are and further testing of intronic regions within this gene would be required to gain a better understanding.  We will present our data of screening for the 10Mb inversion and the exon 2 to 6 inversion in mutation-negative Lynch syndrome patients to determine whether these are common inversions and whether a more universal screening method should be developed to identify other inversions within the MSH2 gene.


Anna Ritchie is a medical scientist in the Molecular Genetics laboratory within VCGS pathology in Melbourne.  She is a Grade 2 scientist, obtaining her HGSA membership in 2011, and has been part of the Molecular Genetics team for over 12 years.  Currently, her main role involves the management of the Next Generation Sequencing (NGS) service for Cancer patients, which includes the testing, analysis, curation and reporting of cancer diagnostic patients.  Previously she has been involved with the testing and reporting for Cystic Fibrosis, Mitochondrial disorders, Duchenne/Becker Muscular Dystrophy and predictive testing for various cardiac conditions and cancers

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