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PALB2 has been implicated as an autosomal dominant predisposition gene for familial ovarian cancer. A large-scale NGS study of 429 ovarian carcinoma cases versus 557 controls identified germline truncation variants in Fanconi pathway genes, with enrichment of rare PALB2 alleles in 20% of cases (PMID:24448499).
Autosomal dominant inheritance is supported by segregation of a novel PALB2 exon 13 tandem duplication in a hereditary breast and ovarian cancer family, co-segregating with disease in ≥3 affected relatives (PMID:27757719).
Case–control analysis revealed at least 9 distinct PALB2 variants in ovarian cancer patients, including truncating alleles and missense changes. Notably, the frameshift variant c.1240C>T (p.Arg414Ter) recurred among ovarian cases (PMID:24448499).
Functional assays demonstrate that PALB2 serves as the molecular scaffold linking BRCA1 and BRCA2 to RAD51 during homologous recombination. Disruption of PALB2 impaired HR repair in cell models and accelerated tumorigenesis in Palb2-deficient mice (PMID:19369211; PMID:23657012).
Integration of genetic and experimental data yields a Strong gene–disease association: multiple truncating and missense variants in ovarian cohorts, familial segregation, and concordant HR defect models. Testing PALB2 in hereditary ovarian cancer panels enhances risk stratification and guides targeted surveillance and therapy.
Gene–Disease AssociationStrong9 truncating/missense variants in ovarian cases; segregation in a multiplex family; concordant functional data Genetic EvidenceStrongEnrichment of PALB2 truncating and missense variants in 429 cases vs 557 controls; familial segregation of exon 13 duplication Functional EvidenceModeratePALB2 is a core BRCA1–PALB2–BRCA2 scaffold in HR; cell and mouse models recapitulate HR defects |