Greg Findlay (@TheGenomeLab) #ASHG22: Von Hippel-Lindau (VHL) is a tumor suppressor gene that is tied to renal cancers (somatic mutations), VHL disease or cancer predisposition (germline mutations).
Greg Findlay (@TheGenomeLab) #ASHG22: >700 VUS in ClinVar. Using saturation genome editing to test all possible variants in a single experiment. Here looking at ~2k variants in VHL.
High correlation between replicates: clean data 👍
High correlation between replicates: clean data 👍
Greg Findlay (@TheGenomeLab) #ASHG22: Nonsense variants only seem to have an impact ("drop out") after Methionine 54.
Missense variants drop out if they occur in a beta sheet (exon 2) or alpha helices (exon 3).
Missense variants drop out if they occur in a beta sheet (exon 2) or alpha helices (exon 3).
Greg Findlay (@TheGenomeLab) #ASHG22: 96% sensitivity for all ClinVar pathogenic SNVs. Only 10% of VUS look like loss-of-function.
Nearly all SNVs in renal cell carcinoma samples score as loss-of-function -- reminder: these are somatic in patients + seen in many samples.
Nearly all SNVs in renal cell carcinoma samples score as loss-of-function -- reminder: these are somatic in patients + seen in many samples.
@TheGenomeLab Greg Findlay (@TheGenomeLab) #ASHG22: Variants seen repeatedly in reference populations (e.g. gnomAD, UKB, TOPMed) are nearly always neutral [nice to see this].
Notes that computational predictors (EVE, REVEL, VARITY, etc) still don't do particularly well compared to this assay.
Notes that computational predictors (EVE, REVEL, VARITY, etc) still don't do particularly well compared to this assay.
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