Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.

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Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods.

Cancer Biol Ther. 2017 May 11;:0

Authors: Arora S, Huwe PJ, Sikder R, Shah M, Browne AJ, Lesh R, Nicolas E, Deshpande S, Hall MJ, Dunbrack RL, Golemis EA

Abstract
The cancer-predisposing Lynch Syndrome (LS) arises from germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1, MSH2, MSH6,and PMS2. A major challenge for clinical diagnosis of LS is the frequent identification of variants of uncertain significance (VUS) in these genes, as it is often difficult to determine variant pathogenicity, particularly for missense variants. Generic programs such as SIFT and PolyPhen-2, and MMR gene-specific programs such as PON-MMR and MAPP-MMR, are often used to predict deleterious or neutral effects of VUS in MMR genes. We evaluated the performance of multiple predictive programs in the context of functional biological data for 15 VUS in MLH1, MSH2, and PMS2. Using cell line models, we characterized VUS predicted to range from neutral to pathogenic on mRNA and protein expression, basal cellular viability, viability following treatment with a panel of DNA-damaging agents, and functionality in DNA damage response (DDR) signaling, benchmarking to wild-type MMR proteins. Our results suggest that the MMR gene-specific classifiers do not always align with the experimental phenotypes related to DDR. Our study highlights the importance of complementary experimental and computational assessment to develop future predictors for the assessment of VUS.

PMID: 28494185 [PubMed - as supplied by publisher]

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