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. 2016 Jul 1;17(1):99.
doi: 10.1186/s12863-016-0407-0.

Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm

Brian Morris  1 , Elisha Hughes  1 , Eric Rosenthal  2 , Alexander Gutin  1 , Karla R Bowles  3
Affiliations

Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm

Brian Morris et al. BMC Genet. .

Abstract

Background: 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). 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.

Methods: Upon 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.

Results: 25,500 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.

Conclusions: We 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.

Keywords: Lynch syndrome; MLH1; MSH2; MSH6; Variant classification.

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Figures

Fig. 1
Fig. 1
Relationship between the proband number required to make an HWA classification call, gene and call type (pathogenic or benign). Fewer probands were required for the classification of MLH1 and MSH2 variants in comparison to MSH6 variants. Generally, fewer probands were also required for classification of benign variants in comparison to pathogenic variants for the same gene
Fig. 2
Fig. 2
HWA graphs illustrating classification calls for select representative variants. The x-axis of each graph indicates the log of the history weighting score and the y-axis indicates the number of control variants
See this image and copyright information in PMC

References

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