GTS5:PALB2-related cancer predisposition syndrome (PALB2): Difference between revisions

The diagnosis of PALB2 related cancer predisposition syndrome is established by identifying a germline pathogenic or likely pathogenic variant in ''PALB2'' using validated molecular genetic testing methods, including multigene hereditary cancer panels, genome sequencing, or targeted familial testing<ref name=":4" /><ref name=":5" />. Testing is typically pursued in individuals with early onset breast cancer, multiple primary malignancies, a personal or family history suggestive of hereditary breast and/or pancreatic cancer, or tumor genomic findings consistent with homologous recombination deficiency that prompt germline evaluation<ref name=":4" /><ref name=":7" />. Once a pathogenic variant is identified, cascade testing of at-risk relatives is recommended<ref name=":5" /><ref name=":8" />.

Pathogenic variants in PALB2 are associated with hereditary breast cancer susceptibility and confer a moderate-to-high lifetime risk of breast cancer, with risk estimates approaching those observed for BRCA2 in some families (Antoniou et al., 2014; Tischkowitz et al., 2017). Female carriers have an estimated 35–58% lifetime risk of breast cancer by age 70, with risk modified by family history and other genetic or environmental factors. PALB2 pathogenic variants are also associated with an increased risk of pancreatic cancer, and emerging evidence suggests a possible association with ovarian cancer, although penetrance for non-breast cancers remains lower and less well defined compared with BRCA1/2 (Yang et al., 2020; NCCN, 2024). Biallelic pathogenic variants in PALB2 cause Fanconi anemia subtype N, characterized by congenital anomalies, bone marrow failure, and childhood cancer predisposition, highlighting the gene’s essential role in DNA repair (Reid et al., 2007). From a molecular standpoint, PALB2 encodes a critical partner of BRCA1 and BRCA2 within the homologous recombination (HR) DNA repair pathway. Loss-of-function variants result in homologous recombination deficiency (HRD), which has therapeutic relevance, as tumors harboring germline or somatic PALB2 pathogenic variants may demonstrate sensitivity to PARP inhibitors and platinum-based chemotherapy (Park et al., 2021; Mateo et al., 2019). Identification of a pathogenic PALB2 variant has important clinical management implications, including enhanced breast cancer surveillance (e.g., annual breast MRI), consideration of risk-reducing strategies, and cascade testing for at-risk relatives, in accordance with established professional guidelines (NCCN, 2024).