Multigene Panel Testing for Hereditary Cancer: What It Adds

From Single Genes to Panels

Sequencing costs have fallen enough that testing 20 to 80 or more genes costs little more than testing one or two. Panels can identify a hereditary cause that a targeted test would miss, for example finding a mismatch-repair variant in someone tested for breast cancer genes.

Studies of patients meeting criteria for one syndrome frequently find pathogenic variants in unexpected genes, which is the main argument for a broader approach.

The Variant-of-Uncertain-Significance Trade-off

Every additional gene analysed increases the chance of finding a variant that cannot yet be classified as pathogenic or benign. Larger panels therefore return more variants of uncertain significance, which can cause anxiety and, if misused, inappropriate management.

A variant of uncertain significance should not change medical management. Only variants classified as pathogenic or likely pathogenic are acted upon.

Gene Content Is Not Standardised

Panels differ between laboratories. Some include only genes with established, actionable risk; others add genes with weaker or uncertain evidence. Testing a gene for which there is no agreed management guidance can produce a result that no one knows how to use.

The genes analysed, and the laboratory's classification framework, are part of interpreting any panel report.

High, Moderate and Uncertain Risk Genes

Panels mix genes with very different risk levels. BRCA1, BRCA2, TP53 and the mismatch-repair genes carry high, well-defined risks. ATM, CHEK2, BRIP1 and others carry moderate risks that are strongly modified by family history. Some genes on panels have risks that are still being defined.

A pathogenic variant in a moderate-risk gene does not carry the same implications as one in a high-risk gene, and management differs accordingly.

Interpretation Notes

Panel results are best returned with genetic counselling that places the specific gene and variant in the context of the person's history and the current evidence.

A negative panel does not exclude hereditary risk, because not all predisposition genes are known and some variant types are hard to detect.

Key Takeaways

• ·Panels detect hereditary causes that single-gene tests miss.
• ·They also return more variants of uncertain significance, which should not change management.
• ·Gene content varies between laboratories and affects how usable a result is.
• ·High-, moderate- and uncertain-risk genes on the same panel are not equivalent.