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Predictive functional assay‐based classification of PMS2 variants in Lynch syndrome
Author(s) -
Rayner Emily,
Tiersma Yvonne,
Fortuno Cristina,
HeesStuivenberg Sandrine,
Drost Mark,
Thompson Bryony,
Spurdle Amanda B.,
Wind Niels
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24387
Subject(s) - pms2 , lynch syndrome , msh6 , msh2 , penetrance , biology , mlh1 , genetics , germline mutation , mutation , bioinformatics , computational biology , dna mismatch repair , gene , dna repair , phenotype
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, represent variants of uncertain significance (VUS). The inability to classify most 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 quantitative tool to improve the classification of VUS in MMR proteins. To derive a formula that translates CIMRA assay results into the odds of pathogenicity (OddsPath) for VUS in PMS2 we used a set of clinically classified PMS2 variants supplemented by inactivating variants that were generated by an in cellulo genetic screen, as proxies for cancer‐predisposing variants. Validation of this OddsPath revealed high predictive values for benign and predisposing PMS2 VUS. We conclude that the OddsPath provides an integral metric that, following the other, higher penetrance, MMR proteins MSH2, MSH6 and MLH1 can be incorporated as strong evidence type 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).