Back to Search
Start Over
Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk
- Source :
- American Journal of Human Genetics
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Summary The 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.
- Subjects :
- variants of uncertain significance
DNA mismatch repair
Functional testing
Mutation, Missense
Computational biology
Biology
Article
deep mutational scanning
Genetics
medicine
Humans
cancer
Missense mutation
Genetic Predisposition to Disease
Uncertain significance
Massively parallel
Genetics (clinical)
medicine.disease
Colorectal Neoplasms, Hereditary Nonpolyposis
Lynch syndrome
MSH2
genotype-phenotype
HEK293 Cells
MutS Homolog 2 Protein
Functional status
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....b0807246bb9be1be7c3d759d976ccf61