The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk
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KeywordsBreast cancer predisposition Breast cancer genetic risk factor PALB2 p.Leu939Trp VUS
Missense mutations in breast cancer predisposition genes are a substantial clinical problem. These are usually considered variants of uncertain significance (VUS) until genetic, clinical, and functional data provide statistical evidence for reclassification as pathogenic or neutral.
Recently, Park et al.  suggested that the WD40 domain of the protein encoded by the breast cancer predisposition gene PALB2 may scaffold RAD51C, RAD51, and BRCA2 proteins into a complex involved in DNA repair mediated by homologous recombination (HR). The authors studied the effect of p.Leu939Trp and other missense mutations located within the PALB2 WD40 domain that had been identified in the germline of women with breast cancer. They reported that the p.Leu939Trp mutation resulted in altered PALB2–BRCA2 binding, decreased capacity for DNA double-strand break-induced HR, and increased sensitivity to ionizing radiation. Based on these observations and their assertion that this mutation occurs more frequently in women with breast cancer than in unaffected women, Park et al.  concluded that the p.Leu939Trp mutation may be pathogenic and proposed that their assays could be used for the functional characterization of other PALB2 missense variants.
Results from functional assays with undefined sensitivity and specificity are not sufficient to classify VUS. In this instance, the p.Leu939Trp mutation may have some influence on response to ionizing radiation but it appears to have little to no impact on HR-mediated DNA repair. In conclusion, our findings suggest that the PALB2 p.Leu939Trp mutation should be classified as a neutral variant with no clinical relevance to risk of breast cancer.
FJC performed the functional analyses. IC and PP wrote the manuscript. All authors contributed to and critically revised the manuscript and approved the final manuscript.
The authors declare that they have no competing interests.
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