Improving Detection and Interpretation in Hereditary Cancer Testing

In short, patients and their families need faster, clearer and more comprehensive answers. Standard-of-care panels often miss complex structural variants, pseudogenes and epigenetic changes, contributing to diagnostic yields of only 15–25% in many cohorts. In addition, legacy workflows frequently rely on multiple separate assays, adding cost, complexity and delays. Samples may need to be sent to centralized facilities for batching, leading to longer turnaround times and in many cases, the results are inconclusive, leaving families without clear answers.

The HCP was developed to consolidate these analyses into a single, information-rich workflow with no batching required, directly addressing these limitations and improving access to more comprehensive insights. The HCP is currently for research use only and not for use in diagnostic procedures.

Oxford Nanopore’s molecular sensing platform uniquely enables analysis of DNA (or RNA) fragments spanning short to ultra-long lengths, providing comprehensive coverage across genes associated with hereditary cancers. With adaptive sampling, target regions are enriched directly on the device while simultaneously generating low-pass whole-genome data, supporting both focused and genome-wide interrogation. This approach enhances detection of challenging variant types, including large insertions, deletions, repetitive elements and structural variants that are often missed by short-read platforms.

In parallel, the technology captures DNA methylation profiles without additional sample preparation, enabling integrated genetic and epigenetic insights within a single workflow.

Haplotype phasing reveals whether variants occur on the same chromosome (cis) or opposite chromosomes (trans). This distinction is critical in hereditary cancer syndromes. For example, knowing whether pathogenic variants are present on both gene copies can change risk assessment, clinical interpretation and management decisions for patients and their families. Nanopore’s ability to directly phase long reads brings this insight into a single consolidated hereditary cancer panel and has the potential to improve patient management decisions in the future.

The research use only panel targets key hereditary cancer genes with immediate clinical relevance, including BRCA1/2 (hereditary breast and ovarian cancers), MLH1/MSH2 (Lynch syndrome) and VHL (Von Hippel–Lindau disease). Performance studies confirmed robust detection of large BRCA1/2 deletions, exon-level MSH2 deletions and complex indels in VHL – variants that are critical for disease insights but often missed by standard methods.

Notably, early beta testing presented at HGSA and AMP showed that the HCP panel could reliably distinguish PMS2 mutations from its pseudogene PMS2CL, a challenge that typically requires labor-intensive secondary assays. These results illustrate how the panel can immediately improve and streamline workflows for hereditary cancer insights.

By enabling comprehensive detection of variants and methylation in a single assay, the HCP offers the potential to simplify workflows and increase diagnostic yield. As evidence from clinical labs builds, this approach could support updates to guidelines that emphasize the importance of structural variant detection, phasing and epigenetics in hereditary cancer testing. In the longer term, the accessibility of nanopore workflows could help decentralize testing and broaden adoption in diverse healthcare settings.