Fig. 6: Classification of PALB2 missense variants from ClinVar by impact in site-saturation functional screens.

a Radial bar chart of PALB2 SNVs reported in ClinVar (as of June, 2025) (left), pie chart showing the distribution PALB2 missense VUS from ClinVar which were examined in site-saturation functional screens and are located in the CC and WD40 domains. Variants in the pre-CC (start codon to first codon of the CC domain) and middle regions were not examined in these screens. Histogram showing the frequency distribution of depletion scores of PALB2 CC and WD40 VUS from ClinVar (right). Dashed lines indicate thresholds from ‘Fig. 4a’, which were used to classify PALB2 CC and WD40 VUS from ClinVar as either functional (green), intermediate (orange) or damaging (red). b Schematic representation of the PALB2 protein in which amino acid numbers are shown to specify the evolutionarily conserved functional domains of PALB2 (bottom). PALB2 variants are color-coded as indicated. c DR-GFP HR assay in Trp53^KO/Palb2^KO mES cells expressing the indicated PALB2 variants from (b). HR efficiencies were normalized to the WT PALB2 condition which was set to 100%. Ev is the empty vector control. d PARPi sensitivity assay using Trp53^KO/Palb2^KO mES cells expressing the indicated PALB2 variants variants from (b) and (c). Values indicate the relative resistance to 0.5 μM PARPi treatment with the WT PALB2 condition set to 100%. In c and d, mean is shown, n  =  2 biological replicates, dots represent individual data points. Source data are provided as a Source Data file.