NDLI: Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

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Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Content Provider	Europe PMC
Author	Jia, Xiaoyan Burugula, Bala Bharathi Chen, Victor Lemons, Rosemary M. Jayakody, Sajini Maksutova, Mariam Kitzman, Jacob O.
Copyright Year	2020
Abstract	SummaryThe lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed “variants of uncertain significance” (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians’ interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7820803&blobtype=pdf
ISSN	00029297
Journal	American Journal of Human Genetics [Am J Hum Genet]
Volume Number	108
DOI	10.1016/j.ajhg.2020.12.003
PubMed Central reference number	PMC7820803
Issue Number	1
PubMed reference number	33357406
e-ISSN	15376605
Language	English
Publisher	Elsevier
Publisher Date	2020-12-23
Access Restriction	Open
Rights License	This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). © 2020 The Author(s)
Subject Keyword	MSH2 Lynch syndrome variants of uncertain significance cancer genotype-phenotype DNA mismatch repair deep mutational scanning
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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