A germline PALB2 pathogenic variant identified in a pediatric high-grade glioma.

PALB2 (partner and localizer of BRCA2) gene encodes a protein that colocalizes
with BRCA2 in nuclear foci and likely permits the stable intranuclear localization
and accumulation of BRCA2PALB2 plays a critical role in maintaining genome integrity through its role in
the Fanconi anemia and homologous recombination DNA repair pathways. It has
a known loss-of-function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi
anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and
pancreatic cancer (Science 324: 217; Cancer Res 71: 2222-2229; N Engl J Med 371: 497-506). Heterozygous germline PALB2 mutations have also been observed in patients with medulloblastoma (Lancet Oncol 19: 785-798). However, PALB2-related cancer predisposition to high-grade gliomas has not been reported.
Here we report a germline PALB2 pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found
in a pediatric patient with high-grade glioma. This variant was first
identified by tumor sequencing using the Children’s Hospital of
Philadelphia (CHOP) Comprehensive Solid Tumor Panel and then confirmed to
be a germline change using the CHOP Comprehensive Hereditary Cancer Panel
on DNA from a blood sample of this patient. Parental studies showed that
this variant was paternally inherited. Further studies are needed to
illustrate if pathogenic variants in PALB2 convey increased risk to developing brain tumor. This case also highlights
the potential of identifying germline mutation through tumor sequencing.