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Functional assay-based classification of PMS2 variants in Lynch Syndrome
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  • Emily Rayner,
  • Yvonne Tiersma,
  • Cristina Fortuno,
  • Sandrine van Hees-Stuivenberg,
  • Mark Drost,
  • Bryony Thompson,
  • Amanda Spurdle,
  • Niels de Wind
Emily Rayner
Leiden University Medical Center

Corresponding Author:[email protected]

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Yvonne Tiersma
Leiden University Medical Center
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Cristina Fortuno
QIMR Berghofer Medical Research Institute
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Sandrine van Hees-Stuivenberg
Leiden University Medical Center
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Mark Drost
Leiden University Medical Center
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Bryony Thompson
The Royal Melbourne Hospital
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Amanda Spurdle
QIMR Berghofer Medical Research Institute
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Niels de Wind
Leiden University Medical Center
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Abstract

The large majority of germline alterations identified in the DNA mismatch repair (MMR) gene PMS2, a low-penetrance gene for the cancer predisposition Lynch Syndrome (LS, OMIM 120435), represent variants of unknown significance (VUS). The inability to assess pathogenicity of such VUS interferes with personalized healthcare. The complete in vitro MMR activity (CIMRA) assay, that only requires sequence information on the VUS, provides a functional analysis-based tool suited for VUS classification. To derive a formula that translates CIMRA assay results for PMS2 VUS into the odds of pathogenicity (OddsPath), we used a set of clinically classified PMS2 variants, supplemented by inactivating variants generated by an in cellulo genetic screen, as proxies for pathogenic variants. Validation of this OddsPath revealed very high predictive values for PMS2 VUS. We conclude that this OddsPath provides an integral metric that, similar to the other, higher penetrance, MMR proteins MSH2, MLH1 and MSH6, can be incorporated into the upcoming criteria for MMR gene VUS classification of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). This will represent a seminal step forward in enabling personalized healthcare for individuals suspected of LS and their relatives.
02 Nov 2021Submitted to Human Mutation
11 Nov 2021Submission Checks Completed
11 Nov 2021Assigned to Editor
24 Nov 2021Reviewer(s) Assigned
13 Dec 2021Review(s) Completed, Editorial Evaluation Pending
17 Dec 2021Editorial Decision: Revise Major
04 Mar 20221st Revision Received
07 Mar 2022Assigned to Editor
07 Mar 2022Submission Checks Completed
08 Mar 2022Reviewer(s) Assigned
25 Mar 2022Review(s) Completed, Editorial Evaluation Pending
04 Apr 2022Editorial Decision: Revise Minor
07 Apr 20222nd Revision Received
08 Apr 2022Assigned to Editor
08 Apr 2022Submission Checks Completed
08 Apr 2022Review(s) Completed, Editorial Evaluation Pending
20 Apr 2022Editorial Decision: Accept