SO04: Targeted NGS of 22 mismatch repair genes identifies LS families

B.A. Talseth-Palmer1, 2,D.C. Bauer3, W. Sjursen4 5, T.J. Evans1, 2, M. McPhillips6, A. Proietto7, 8, G. Otton7, 8, A.D. Spigelman9, 10, R.J. Scott1,2,6.

1 – School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia.2 –  Centre for Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales, Australia.3 – CSIRO Digital Productivity, Sydney, New South Wales, Australia. 4 – Department of Laboratory Medicine Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway. 5 – Department of Pathology and Medical Genetics, St Olavs University Hospital, Trondheim, Norway. 6 – Hunter Area Pathology Service, Pathology North, Hunter New England Area Health, Newcastle, New South Wales, Australia. 7 – Hunter Centre for Gynaecological Cancer, Hunter New England Area Health, Newcastle, New South Wales, Australia. 8 – School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia. 9 – Hunter Family Cancer Service, Hunter New England Area Health, Newcastle, New South Wales, Australia. 10 – St Vincent’s Hospital Clinical School, University of NSW and Hospital Cancer Genetics Clinic, The Kinghorn Cancer Centre, Sydney, New South Wales, Australia.


Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumours, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches.


Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation.


We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance


In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant.