They don't care that republicans still get cancer and other diseases and fall on hard times and have special-needs kids. This was the deal. "We will hurt the people you hate even if it hurts you" and half the country signed up in blood

We hope this serves as a useful resource to assist with rare variant interpretation, and believe our approach can be extended to other DNA repair factors where the #VUS burden challenges the actionability of genetic testing. 5/5

We examined individual-level clinical phenotypes of MUTYH biallelic individuals, in collaboration with a clinical lab (Ambry Genetics). Individuals with a pathogenic+missnse VUS had much higher polyposis risk -- when their VUS scored as abnormal by our assay 4/5

Our map perfectly separates known pathogenic and benign variants from ClinVar, and based upon clinical calibration, it provides ‘strong’ evidence to resolve the >1000 standing clinical missense VUS 3/5

To measure MUTYH variant function, we leveraged a reporter containing a mispair of 8oxoguanine w/ adenine, the substrate that MUTYH recognizes. AFAIK, this is the first MAVE coupled to a direct readout of repair at an DNA oxidative damage lesion. 2/5

In short: SpliceAI and Pangolin generally performed well. Splicing effects are harder to predict in exons vs introns. Gene model annotation really matters!  We think the places where they disagree will be interesting targets for future MPSAs.  3/3

This leverages MPSAs from our group and others. Cathy led several of these, including one published this past summer in WT1, a  transcription factor where alt splicing is disrupted in Mendelian forms of nephrotic syndrome www.kireports.org/article/S246...   2/3

Finally, also on Thursday, PB1111 from talented undergrad Kirsten Nishino (also w/ Steve Parker & Adelaide Tovar) examines how environment effects modify transcriptional response using this modular MPRA system 5/5

On Sat, PB1089 from postdoc Adelaide Tovar (& Steve Parker lab) uses a modular MPRA to interrogate enhancer-promoter context and cell type influences on regulatory action 4/5

Also, PB1030 from 2xDr Anthony Scott and colleagues at Ambry Genetics shows how we've calibrated another deep mutational scan of another #LynchSyndrome gene, MLH1, for use in clinical variant interpretation 3/5

Check out these posters on Thurs too! In PB1006, we present a really cool (imho) DMS strategy from postdoc Shelby Hemker which goes beyond drug or viability selections to read out function of DNA repair factor variants 2/5