What actionability of a molecular variant means and how it is classified

A molecular variant is actionable when its presence can change a clinical decision: guiding the choice of a treatment, anticipating resistance, refining a diagnosis or prognosis, or opening the door to a clinical trial. Actionability is not an intrinsic property of the gene or the mutation: it is a statement about the evidence available in a specific context, and it therefore changes with tumour type, line of therapy and time.

This distinction is the source of most misunderstandings when reading a next-generation sequencing report. An NGS panel can return dozens of alterations, and the relevant question for a tumor board is never how many there are, but which ones have consequences and with what degree of support. A variant in a famous gene may be irrelevant in a given tumour, while a less well-known alteration can be decisive if solid evidence exists in that specific setting.

Consensus classification frameworks exist to organise that judgement. Their purpose is not to decide the treatment but to make explicit the level of evidence behind each statement, so that different professionals, in different centres, read the same finding by the same criteria.

The joint framework of the Association for Molecular Pathology (AMP), the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) is the most widely used reference for classifying somatic variants in oncology. Its logic is twofold: it first grades the strength of the evidence supporting a variant and then assigns it to a tier of clinical significance.

Evidence levels are usually ordered into four grades. The highest corresponds to biomarkers included in indications approved by regulatory agencies or set out in established clinical practice guidelines. The next gathers evidence from well-conducted clinical trials or published expert consensus. Below that sit smaller studies or results not yet independently confirmed, and the lowest level holds preclinical data, in vitro functional studies and isolated case reports.

On that basis, variants are grouped into four categories of clinical significance:

• Strong clinical significance: variants with diagnostic, prognostic or therapeutic implications supported by regulatory approvals or established guidelines in the tumour type assessed.
• Potential clinical significance: variants with emerging evidence, or with solid evidence in another tumour type, which may justify considering a clinical trial or off-label use assessed case by case.
• Uncertain clinical significance: variants without sufficient evidence either to affirm or to rule out clinical relevance, common in practice and often poorly communicated.
• Benign or likely benign variants: alterations with no known clinical relevance in the context assessed.

The uncertain-significance category deserves particular attention because it is usually the largest. An uncertain variant is not a negative variant: it is a finding without sufficient support, which may be reclassified when new evidence appears. Documenting that status, rather than omitting it, is part of an honest interpretation.

The ESCAT scale (ESMO Scale for Clinical Actionability of Molecular Targets), proposed by the European Society for Medical Oncology, approaches the problem from another angle. Instead of classifying the variant as a laboratory finding, it grades the maturity of the relationship between a molecular alteration and a targeted drug in a specific tumour type.

Its levels describe a path: from targets with clinical benefit demonstrated in prospective studies and already established in practice, through targets with preliminary clinical evidence requiring confirmation, to situations where benefit has been shown in another tumour, the evidence is only preclinical, or the available data indicate an absence of benefit. There is also a specific consideration for alterations that predict resistance to a treatment.

The result is a reading strongly oriented to the therapeutic conversation: ESCAT answers the question of how much support there is for acting on this target, in this tumour, with this drug.

AMP/ASCO/CAP and ESCAT do not compete: they answer different questions and are used at different moments in the process. The former originates in the molecular pathology laboratory and classifies every variant detected, including those with no therapeutic implication at all. The latter originates in medical oncology and grades the strength of therapeutic targets.

• Object: AMP/ASCO/CAP classifies variants; ESCAT classifies targets tied to a drug and a tumour.
• Scope: AMP/ASCO/CAP covers diagnostic, prognostic and therapeutic implications; ESCAT focuses on therapeutic actionability.
• Typical use: the former structures the molecular report; the latter structures the discussion of treatment options and trials.
• Common ground: both depend on the tumour context and both can change when new evidence is published.

In practice, a report that cites one of the two frameworks without saying which, or that mixes their levels without noting it, creates confusion. Writing “level I” without stating which scale it belongs to is an ambiguity with consequences: levels are not interchangeable between frameworks.

Every actionability classification has a date. Evidence is updated, indications are widened or narrowed and variants are reclassified. That is why recording the version of the sources used — guidelines, knowledge bases, summaries of product characteristics — is part of the clinical content of the report, not administrative metadata: without it, it is impossible to reconstruct why something was stated on the date it was stated.

There are also technical constraints that no scale resolves. The panel used determines what could and could not be detected; allele fraction and sample quality affect confidence in the finding; and in the case of fusions, relevance depends on the genes involved, the breakpoint and whether the functional domain is preserved. An actionability level assigned without that context can be formally correct and clinically misleading.

Finally, the classification does not include the patient. Performance status, previous lines of therapy, central nervous system involvement, comorbidities and concomitant medication can make a theoretically actionable option unviable. The scale organises the evidence; the tumor board decides.

A molecular report that is useful to a tumor board makes four things explicit: what was detected, with what level of evidence and under which framework, in which tumour context that evidence applies, and what information is missing to complete the interpretation. With those four elements, the discussion centres on the patient. Without them, much of the session is spent verifying where statements came from.

That work of structuring and verifying sources is precisely what we address in Sphera OncoCore, which classifies actionability following the AMP/ASCO/CAP framework and links every statement to its source and version so that it can be audited.