Hereditary Central Nervous System/Brain Cancer Panel

About Hereditary Central Nervous System/Brain Cancers

Pediatric brain tumors represent the most common solid cancer in childhood, with a significant genetic component in their development.¹ Approximately 8-19% of pediatric central nervous system (CNS) tumors are associated with germline variants linked to tumor predisposition syndromes (TPS).^1,2 Medulloblastoma, accounting for approximately 20% of pediatric brain cancers, is the most frequent malignant childhood brain tumor and can occur in several TPSs including nevoid basal cell carcinoma syndrome, Li-Fraumeni syndrome, Fanconi anemia, familial adenomatous polyposis, and Rubenstein-Taybi syndrome.^2,3 Other CNS tumors, including choroid plexus tumors, high- and low-grade gliomas, and meningiomas, are also seen in patients with TPSs such as neurofibromatosis type 1, Li-Fraumeni syndrome, and constitutional mismatch repair deficiency. ² Most hereditary pediatric cancer syndromes follow an autosomal dominant inheritance pattern. Causative variants can include both sequence variants and copy number variations. The diagnostic yield of this panel varies significantly based syndrome and clinical presentation.^2,4,5

All genetic tests have limitations. Please refer to our Test Methods page for limitations relevant to this methodology.

PMS2: DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is not typically included in this test but can be ordered separately using test code 6062, if desired. 

POLE: Testing is restricted to the clinically relevant exonuclease domains.

TSC1: This test does not include analysis of TSC1 (NM_000368.4) non-coding exons 1 and 2, as to our knowledge, no sequence variants have been reported in association with TSC1-related disease within this region. However, a limited number of copy number variants (CNVs) have been reported in association with tuberous sclerosis complex (TSC) within this interval (e.g. van den Ouweland et al. 2011. PubMed ID: 20877415; Overwater et al. 2016. PubMed ID: 27406250). If TSC is strongly suspected, TSC1 multiplex ligation-dependent probe amplification (MLPA) may be ordered using test code 2055.

Enhanced Testing

APC: This test includes analysis of the APC promoter 1B region.

MSH2: This testing includes the inversion of exons 1 to 7 in MSH2 (Boland Inversion) and the c.942+3A>T polyalanine repeat variant.

NF1 and PMS2: Deletion and duplication testing for NF1 and PMS2 is performed using NGS, but CNVs detected in these genes are usually confirmed via multiplex ligation- dependent probe amplification (MLPA).

PTEN: This testing includes coverage of the PTEN minimal promoter region (positions –1239 to –765 relative to the start codon).

VHL: This testing includes the VHL E1’ cryptic exon.

The analytical sensitivity of the PGxome platform has been validated at >99% for single nucleotide variants, >95% for indels <49 bp, and >99% for CNV ≥3 exons in size. Sensitivity is reduced in regions with repetitive elements or paralogy.

PGxome® platform: Capture and amplification based Next Generation Sequencing (NGS) is used to sequence the coding regions of nearly all genes and immediate flanking non-coding DNA (± 10 bp) in all available transcripts along with other non-coding regions harboring known disease-causing variants. Results are filtered to defined genes in panel. Reportable variants include both sequence variants and NGS-based detection of copy number variants (CNVs).Variants not meeting our quality threshold through NGS alone are confirmed with an orthogonal method, including but not limited to Sanger and array.All variants within the analyzed genes which are classified as pathogenic, likely pathogenic, risk, or variant of uncertain significance will be reported.