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  1. Mar 2021
    1. Cells reconstituted with WT-PALB2 showed substantially less sensitivity to olaparib than cells expressing p.A1025R and p.I944N (Fig. 4a). Similar results were observed for cisplatin treatment, although the difference in sensitivity was less pronounced (Fig. 4b). p.L24S, p.L1070P, and p.L35P were also associated with greater sensitivity to olaparib (Fig. 4c) and cisplatin (Fig. 4d) than WT-PALB2.

      AssayResult: 0.01 µM: 80; 0.1 µM: 52; 0.8 µM: 18; 1 µM: 5

      AssayResultAssertion: Abnormal

      Approximation: Exact cisplatin concentrations and assay result values not reported; values estimated from Figures 4b and 4d.

    2. WT-PALB2 was associated with robust formation of damage-induced RAD51 foci, whereas the four variants were associated with defective foci formation (Fig. 3d, e).

      AssayResult: 1.5

      AssayResultAssertion: Abnormal

      Approximation: Exact assay result value not reported; value estimated from Figure 3e.

    3. Results for individual PALB2 variants were normalized relative to WT-PALB2 and the p.Tyr551ter (p.Y551X) truncating variant on a 1:5 scale with the fold change in GFP-positive cells for WT set at 5.0 and fold change GFP-positive cells for p.Y551X set at 1.0. The p.L24S (c.71T>C), p.L35P (c.104T>C), p.I944N (c.2831T>A), and p.L1070P (c.3209T>C) variants and all protein-truncating frame-shift and deletion variants tested were deficient in HDR activity, with normalized fold change <2.0 (approximately 40% activity) (Fig. 1a).

      AssayResult: 1.7

      AssayResultAssertion: Abnormal

      StandardErrorMean: 0.84

    4. A total of 84 PALB2 patient-derived missense variants reported in ClinVar, COSMIC, and the PALB2 LOVD database were selected

      HGVS: NM_024675.3:c.3209T>C p.(Leu1070Pro)

    1. Source Data

      AssayResult: 56.67

      AssayResultAssertion: Not reported

      ReplicateCount: 4

      StandardErrorMean: 12.4

      Comment: Exact values reported in “Source Data” file.

    2. Source Data

      AssayResult: 21.79

      AssayResultAssertion: Abnormal

      ReplicateCount: 2

      StandardDeviation: 1.84

      StandardErrorMean: 1.3

      Comment: Exact values reported in “Source Data” file.

    3. We, therefore, analyzed the effect of 48 PALB2 VUS (Fig. 2a, blue) and one synthetic missense variant (p.A1025R) (Fig. 2a, purple)29 on PALB2 function in HR.

      HGVS: NM_024675.3:c.3209T>C p.(L1070P)