These findings show that the HDR assay is an effective method for screening the influence of inherited variants on PALB2 function, that four missense variants impact PALB2 function and may influence cancer risk and response to therapy, and suggest that few inherited PALB2 missense variants disrupt PALB2 function in DNA repair.
PALB2 mutation carriers were also more likely to have family histories of breast and/or ovarian cancer (27.8% vs. 8.4%, p < 0.001) and any types of cancer (57.4% vs. 31.6%, p < 0.001) when compared with non-carriers.
Our results support a pathogenic classification for PALB2 c.3201+5G>T, highlighting the impact of variants causing an imbalanced expression of natural RNA isoforms in cancer susceptibility.
Although PALB2 truncating mutations are rarely identified, segregation analysis and early onset cancer suggest a significant contribution to HBOC susceptibility in the Spanish population.
BReast Cancer Associated proteins 1 and 2 (BRCA1, -2) and Partner and Localizer of BRCA2 (PALB2) protein are tumour suppressors linked to a spectrum of malignancies, including breast cancer and Fanconi anemia.
PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer.
However, from the limited data that exist, PALB2 may be an example of a cancer predisposition gene that does not conform to Knudson's 'two hit' paradigm.
A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older.
PALB2 (partner and localizer of BRCA2) is a cancer predisposing gene recently described that encodes a protein partner of BRCA2 involved in DNA double-strand break repair and cell cycle control.
The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants.
Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development.
We also examine the involvement of PALB2 mutations in the predisposition to cancer and the role of PALB2 in stimulating error-free DNA repair through the FA/HR pathway.
Three patients presented with early onset of cancer, two had BRCA2 mutation c.7007G > A (p.Arg2336His) and one had a novel c.3425del (p.Leu1142Tyrfs*21) PALB2 mutation.