Abstract
BackgroundLynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Accurate classification of variants identified in these genes as pathogenic or benign enables informed medical management decisions. Previously, we developed a clinical History Weighting Algorithm (HWA) for the classification of variants of uncertain significance (VUSs) in BRCA1 and BRCA2. The BRCA1/2 HWA is based on the premise that pathogenic variants in these genes will be identified more often in individuals with strong personal and/or family histories of breast and/or ovarian cancer, while the identification of benign variants should be independent of cancer history. Here we report the development of a similar HWA to allow for classification of VUSs in genes associated with Lynch syndrome using data collected through both syndrome-specific and pan-cancer panel testing.MethodsUpon completion of algorithm development, the HWA was tested using simulated variants constructed from 79,214 probands, as well as 379 true variants. Positive (PPV) and negative predictive values (NPV) were calculated on a per gene basis.Results25,500 pathogenic and 50,500 benign simulated variants were analyzed using the HWA and the PPVs and NPVs for each gene were greater than 0.997 and 0.999, respectively. The HWA was also evaluated using 100 trials for each of the 379 true variants. PPVs of >0.998 and NPVs of >0.999 were obtained for all genes.ConclusionsWe have developed and implemented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome. The work presented here demonstrates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.
Highlights
Lynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
We have previously described the development and validation of a clinical History Weighting Algorithm (HWA) designed to aid in the reclassification of variants identified in the BRCA1 and BRCA2 genes, which are associated with Hereditary Breast and Ovarian Cancer syndrome (HBOC) [7]
We report here on the development of a HWA to allow for classification of variant of uncertain significance (VUS) in Lynch syndrome (LS)-associated genes using data collected through both syndrome-specific and pancancer panel testing
Summary
Lynch syndrome is a hereditary cancer syndrome associated with high risks of colorectal and endometrial cancer that is caused by pathogenic variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). As is the case for many of the genes responsible for hereditary cancer syndromes, analysis of the LS-associated MMR genes frequently results in the identification of variants that can reliably be predicted to result in loss of Morris et al BMC Genetics (2016) 17:99 function (LOF) of the encoded protein due to premature truncation or other significant structural disruptions. These LOF variants are presumed to be pathogenic, and causative of LS [4]. This process can take years, or even decades, in the case of rare variants
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