How to Read Your NGS Report
A plain-language guide to the core components of a comprehensive genomic profiling report and the principles used to translate genomic data into clinical decisions.
A genomic profiling report is not merely a list of mutations. It is a biological snapshot of a tumor at a specific moment in its evolution.
The first page of an NGS report typically highlights selected findings and possible treatment options. A meaningful interpretation, however, requires looking beyond the summary. The clinical significance of any finding depends on its biological context, technical reliability, strength of evidence, and its relationship to the specific tumor type and disease stage.
The first page highlights selected findings and options. A meaningful interpretation requires looking beyond the summary — at biological context, technical reliability, and the strength of evidence.
The main components of an NGS report
A comprehensive genomic profiling (CGP) report presents several types of information in layers. Reading the report well means knowing what each layer can — and cannot — tell you.
1Genomic alterations
The variant list forms the foundation of the report, but individual alterations should never be interpreted in isolation.
Variant Allele Frequency VAF
VAF refers to the proportion of sequencing reads that contain a given alteration. In clinical practice, it can help answer important questions:
- Is the alteration most likely clonal or subclonal?
- Could it represent an important tumor driver, or an emerging resistant clone?
- Is the finding biologically significant enough to influence treatment decisions?
Tumor purity
Tumor purity refers to the proportion of tumor cells present in the sample analyzed. Low tumor content can reduce the sensitivity of testing and cause clinically meaningful alterations to be missed. For this reason, a negative result does not always mean that a genomic alteration is absent.
Germline and somatic alterations
Some alterations arise only in tumor cells (somatic), while others may be inherited and present in every cell of the body (germline). Distinguishing between the two matters not only for treatment planning but also for hereditary cancer risk assessment and family counseling.
Variant classification
Not every genomic finding carries the same level of certainty. Variants are commonly classified as:
- Pathogenic
- Likely Pathogenic
- Variant of Uncertain Significance (VUS)
Understanding these categories is essential, because most VUS findings should not, on their own, guide treatment decisions.
2Biomarkers beyond individual mutations
Modern genomic reports frequently include broader biomarkers that provide additional biological and therapeutic information.
Tumor Mutational Burden TMB
TMB estimates the number of mutations present in the tumor genome and, in selected settings, may have implications for immunotherapy.
Microsatellite Instability and Mismatch Repair Deficiency MSI · dMMR
These biomarkers reflect defects in DNA repair mechanisms and can predict sensitivity to immune checkpoint inhibitors across multiple tumor types.
Homologous Recombination Deficiency HRD
HRD reflects disruption of specific DNA repair pathways and can influence the use of PARP inhibitors in selected cancers.
Loss of Heterozygosity LOH
LOH measures genomic loss events and can contribute to the assessment of homologous recombination deficiency.
3Translating genomic findings into clinical decisions
The most important question is rarely:
“Which mutation was found?”
The more meaningful question is:
“Does this finding change clinical management?”
Clinical interpretation requires considering:
- Therapeutic relevance
- Tumor-specific evidence
- Strength of supporting data
- Available targeted therapies
- Potential clinical trial opportunities
- Known resistance mechanisms
A biomarker that is actionable in one tumor type is not necessarily actionable in another.
How we read an NGS report
At NGS Advisory, every case is evaluated using a structured framework: six questions asked in sequence before any conclusion is reached.
1Is the finding technically reliable?
Before discussing biological significance, we assess sequencing quality, coverage, tumor purity, and the technical limitations of the test.
2Is the alteration biologically significant?
We distinguish between:
- Driver alterations
- Passenger alterations
- Resistance mechanisms
- Possible clonal hematopoiesis (CHIP)
- Variants of uncertain significance
3Is the finding clinically relevant in this tumor type?
An alteration may be targetable in one cancer and clinically irrelevant in another. Tumor context matters.
4What is the level of evidence?
We grade findings against established evidence frameworks, including:
- AMP / ASCO / CAP classification
- ESCAT classification
- Regulatory approvals
- Prospective clinical trial data
Not all actionable findings carry the same level of confidence.
5Where is the patient in the course of disease?
The same biomarker can have very different implications depending on treatment line, prior therapies, acquired resistance, and disease evolution.
6What is the strategy beyond the next treatment?
Precision oncology is not only about selecting a single treatment. It also involves anticipating resistance mechanisms, sequencing future options, and identifying opportunities that may become relevant at later stages of the patient's journey.
Why a second review can matter
Two experienced clinicians can reach different conclusions from the same genomic report. This is not necessarily a flaw in the data; it reflects the complexity of interpreting genomic information under clinical uncertainty.
A meaningful interpretation requires integrating:
- Molecular pathology
- Tumor biology
- Genomic context
- Clinical evidence
- Therapeutic strategy
A structured expert review makes the reasoning process transparent and allows conclusions to be critically evaluated rather than simply accepted.
Precision oncology begins with interpretation.
Genomic testing generates data. Clinical value emerges only when that data is translated into a biologically and clinically coherent strategy.
Understanding how to read an NGS report is the first step in that process.
This content is for educational purposes only. It does not constitute individual medical advice and does not replace the judgment of the treating physician.
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