Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome

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Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. / Drost, Mark; Tiersma, Yvonne; Glubb, Dylan; Kathe, Scott; van Hees, Sandrine; Calléja, Fabienne; Zonneveld, José B.M.; Boucher, Kenneth M.; Ramlal, Renuka P.E.; Thompson, Bryony A.; Rasmussen, Lene Juel; Greenblatt, Marc S.; Lee, Andrea; Spurdle, Amanda B.; Tavtigian, Sean V.; de Wind, Niels.

In: Genetics in Medicine, Vol. 22, 2020, p. 847–856.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Drost, M, Tiersma, Y, Glubb, D, Kathe, S, van Hees, S, Calléja, F, Zonneveld, JBM, Boucher, KM, Ramlal, RPE, Thompson, BA, Rasmussen, LJ, Greenblatt, MS, Lee, A, Spurdle, AB, Tavtigian, SV & de Wind, N 2020, 'Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome', Genetics in Medicine, vol. 22, pp. 847–856. https://doi.org/10.1038/s41436-019-0736-2

APA

Drost, M., Tiersma, Y., Glubb, D., Kathe, S., van Hees, S., Calléja, F., Zonneveld, J. B. M., Boucher, K. M., Ramlal, R. P. E., Thompson, B. A., Rasmussen, L. J., Greenblatt, M. S., Lee, A., Spurdle, A. B., Tavtigian, S. V., & de Wind, N. (2020). Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. Genetics in Medicine, 22, 847–856. https://doi.org/10.1038/s41436-019-0736-2

Vancouver

Drost M, Tiersma Y, Glubb D, Kathe S, van Hees S, Calléja F et al. Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. Genetics in Medicine. 2020;22:847–856. https://doi.org/10.1038/s41436-019-0736-2

Author

Drost, Mark ; Tiersma, Yvonne ; Glubb, Dylan ; Kathe, Scott ; van Hees, Sandrine ; Calléja, Fabienne ; Zonneveld, José B.M. ; Boucher, Kenneth M. ; Ramlal, Renuka P.E. ; Thompson, Bryony A. ; Rasmussen, Lene Juel ; Greenblatt, Marc S. ; Lee, Andrea ; Spurdle, Amanda B. ; Tavtigian, Sean V. ; de Wind, Niels. / Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome. In: Genetics in Medicine. 2020 ; Vol. 22. pp. 847–856.

Bibtex

@article{f38bb7b8e7e148f5998e392227d7c078,
title = "Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome",
abstract = "Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes{\textquoteright} rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.",
keywords = "DNA mismatch repair, functional analysis-based classification, Lynch syndrome, MSH6, variants of uncertain significance",
author = "Mark Drost and Yvonne Tiersma and Dylan Glubb and Scott Kathe and {van Hees}, Sandrine and Fabienne Call{\'e}ja and Zonneveld, {Jos{\'e} B.M.} and Boucher, {Kenneth M.} and Ramlal, {Renuka P.E.} and Thompson, {Bryony A.} and Rasmussen, {Lene Juel} and Greenblatt, {Marc S.} and Andrea Lee and Spurdle, {Amanda B.} and Tavtigian, {Sean V.} and {de Wind}, Niels",
year = "2020",
doi = "10.1038/s41436-019-0736-2",
language = "English",
volume = "22",
pages = "847–856",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome

AU - Drost, Mark

AU - Tiersma, Yvonne

AU - Glubb, Dylan

AU - Kathe, Scott

AU - van Hees, Sandrine

AU - Calléja, Fabienne

AU - Zonneveld, José B.M.

AU - Boucher, Kenneth M.

AU - Ramlal, Renuka P.E.

AU - Thompson, Bryony A.

AU - Rasmussen, Lene Juel

AU - Greenblatt, Marc S.

AU - Lee, Andrea

AU - Spurdle, Amanda B.

AU - Tavtigian, Sean V.

AU - de Wind, Niels

PY - 2020

Y1 - 2020

N2 - Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes’ rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

AB - Purpose: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. Methods: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes’ rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. Results: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. Conclusion: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

KW - DNA mismatch repair

KW - functional analysis-based classification

KW - Lynch syndrome

KW - MSH6

KW - variants of uncertain significance

U2 - 10.1038/s41436-019-0736-2

DO - 10.1038/s41436-019-0736-2

M3 - Journal article

C2 - 31965077

AN - SCOPUS:85078125457

VL - 22

SP - 847

EP - 856

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -

ID: 236668935