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Cold Spring Harb Perspect Med. 2019 Nov 1;9(11). pii: a036228. doi: 10.1101/cshperspect.a036228.

The Impact of Genetic Variants on PTEN Molecular Functions and Cellular Phenotypes.

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Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
Department of Bioengineering, University of Washington, Seattle, Washington 98195, USA.
Genetic Networks Program, CIFAR, Toronto, Ontario, M5G 1M1, Canada.


Phosphatase and tensin homolog (PTEN) is a tumor suppressor that directly regulates a diverse array of cellular phenotypes, including growth, migration, morphology, and genome stability. How a single protein impacts so many important cellular processes remains a fascinating question. This question has been partially resolved by the characterization of a slew of missense variants that alter or eliminate PTEN's various molecular functions, including its enzymatic activity, subcellular localization, and posttranslational modifications. Here, we review what is known about how PTEN variants impact molecular function and, consequently, cellular phenotype. In particular, we highlight eight informative "sentinel variants" that abrogate distinct molecular functions of PTEN. We consider two published massively parallel assays of variant effect that measured the effect of thousands of PTEN variants on protein abundance and enzymatic activity. Finally, we discuss how characterization of clinically ascertained variants, establishment of clinical sequencing databases, and massively parallel assays of variant effect yield complementary datasets for dissecting PTEN's role in disease.

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