Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome.

ABSTRACT:

Background

Lynch syndrome (LS) is a cancer predisposition syndrome affecting more than 1 in every 300 individuals worldwide. Clinical genetic testing for LS can be life-saving but is complicated by the heavy burden of variants of uncertain significance (VUS), especially missense changes.

Result

To address this challenge, we leverage a multiplexed analysis of variant effect (MAVE) map covering >94% of the 17,746 possible missense variants in the key LS gene MSH2. To establish this map's utility in large-scale variant reclassification, we overlay it on clinical databases of >15,000 individuals with LS gene variants uncovered during clinical genetic testing. We validate these functional measurements in a cohort of individuals with paired tumor-normal test results and find that

SUBMITTER: Scott A 

PROVIDER: S-EPMC9773515 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature