Interpreting the clinical significance of mismatch repair gene sequence variants

Thompson, Bryony Ann (2014). Interpreting the clinical significance of mismatch repair gene sequence variants PhD Thesis, School of Medicine, The University of Queensland. doi:10.14264/uql.2015.22

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Author Thompson, Bryony Ann
Thesis Title Interpreting the clinical significance of mismatch repair gene sequence variants
School, Centre or Institute School of Medicine
Institution The University of Queensland
DOI 10.14264/uql.2015.22
Publication date 2014-11-30
Thesis type PhD Thesis
Open Access Status Other
Supervisor Amanda Spurdle
Sean Tavtigian
Daniel Buchanan
Total pages 350
Language eng
Subjects 1112 Oncology and Carcinogenesis
1117 Public Health and Health Services
Formatted abstract
The clinical classification of inherited nucleotide sequence variants identified in disease-related genes has a direct impact on the clinical management of patients and their families. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). However, ~30% of MMR gene variants identified in suspected Lynch cases are of uncertain clinical significance, which constitutes a challenge for genetic counselling and clinical management of families. In the past there has been no uniform system to tackle these variants, and mainly ad hoc methods have been utilized to determine if they are disease causing.

In collaboration with the multi-disciplinary International Society for Gastrointestinal Hereditary Tumours Variant Interpretation Committee (InSiGHT VIC), we have developed a standardized five-tiered classification scheme to classify variants in the MMR genes, which is linked to clinical recommendations for patient management. The rules incorporate validated interpretations of clinical and functional qualitative data and quantitative measures of pathogenicity.

The multifactorial likelihood model approach was initially developed for the evaluation of sequence variants in the BRCA1/2 cancer predisposition genes. It was adapted for MMR gene variants to provide a quantitative measure of risk in the form of probability of pathogenicity. Estimates of prior probability of pathogenicity based on evolutionary sequence conservation and physicochemical characteristics of predicted alterations were combined with variant segregation information and tumour features. Microsatellite instability (MSI) and somatic BRAF V600E tumour data for unselected colorectal cancer probands of known pathogenic variant status were used to derive likelihood ratios (LR) for tumour characteristics using the Colon Cancer Family Registry resource. The LR in favour of pathogenicity was estimated to be ~12-fold for a MSI and BRAF V600E mutation-negative colorectal tumour. Our findings provide a working multifactorial likelihood model for classifications that carefully considers mode of ascertainment for gene testing.

Using both published and unpublished qualitative and quantitative evidence we led efforts by the VIC to apply the refined scheme to 2,360 unique sequence alterations and disseminated online through the publically accessible InSiGHT database. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. Furthermore, a framework that can be transferred to variant classification in other disease/cancer predisposition genes has been developed.
Keyword Lynch syndrome
Mismatch repair genes
Unclassified variants
Clinical genetics
Sequence variant

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Created: Fri, 21 Nov 2014, 14:52:58 EST by Bryony Thompson on behalf of Scholarly Communication and Digitisation Service