Reading your results: from a five-letter classification to a single line of code
A hereditary-cancer report turns a sequencer's output into a clinical verdict. This explainer walks the ACMG/AMP 5-tier scale — pathogenic to benign — unpacks what a VUS really means (and why it can change), and decodes the mono notation like c.68_69delAG that names a variant precisely. Educational only; a clinician or genetic counsellor interprets your own report.
What the report is actually telling you
A germline panel does not return a yes/no. For every variant it finds, the laboratory weighs evidence — population frequency, computational predictions, functional studies, family segregation, de novo occurrence — and places the variant on a standardised five-point scale published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP, 2015). Each line on your report carries three things: a gene (e.g. BRCA1), a variant in HGVS notation (e.g. c.68_69delAG), and a classification. The classification is what drives — or, critically, does not drive — clinical action.
The ACMG/AMP five tiers
Criteria split into pathogenic evidence (weighted very-strong PVS1, strong PS1–4, moderate PM1–6, supporting PP1–5) and benign evidence (stand-alone BA1, strong BS1–4, supporting BP1–6). The combination rules sort a variant into one of these five tiers.
- Pathogenic (P)
- Disease-causing with ~99% certainty. Enough strong evidence (e.g. a
PVS1null variant plus supporting data) that it can inform screening, surgery, and cascade testing of relatives. - Likely pathogenic (LP)
- ~90% certainty of being disease-causing. Generally managed clinically the same way as pathogenic, but the residual uncertainty is acknowledged in counselling.
- Uncertain significance (VUS)
- Evidence is conflicting or insufficient to call the variant either way. A
VUSshould not be used to change medical management — decisions rest on personal and family history instead. - Likely benign (LB)
- Probably harmless (~90% certainty benign). No screening or surgical action follows from it.
- Benign (B)
- Considered harmless — for example a common polymorphism with a stand-alone
BA1high population frequency. Reported for completeness, not for action.
How each tier maps to evidence and action
A simplified view of how the ACMG/AMP framework translates evidence strength into a label and into what happens next. Your laboratory and clinician apply the full criteria; this is orientation, not a substitute for the report.
| Tier | Indicative certainty | Typical evidence pattern | Used in clinical decisions? |
|---|---|---|---|
| Pathogenic (P) | ~99% disease-causing | e.g. PVS1 + strong/moderate support | Yes — screening, risk-reducing options, cascade testing |
| Likely pathogenic (LP) | ~90% disease-causing | Strong + moderate criteria, short of P | Yes — generally managed as pathogenic |
| Uncertain significance (VUS) | Indeterminate | Conflicting or insufficient evidence | No — manage on personal/family history; do not offer cascade testing |
| Likely benign (LB) | ~90% benign | Supporting/strong benign criteria | No |
| Benign (B) | ~99% benign | Stand-alone BA1 (high allele frequency) | No |
Table 1. ACMG/AMP 5-tier classification, indicative certainty, and clinical use. Thresholds per ACMG/AMP 2015; management guidance per NCCN 2024.
What <code>c.68_69delAG</code> actually says
The mono string on your report is HGVS (Human Genome Variation Society) nomenclature — a precise, reproducible way to name a variant. Read NM_007294.4(BRCA1):c.68_69delAG left to right: a reference transcript (NM_007294.4), the gene (BRCA1), then c. for coding-DNA coordinates, 68_69 for the position, and delAG for a deletion of two nucleotides. At the protein level it becomes p.Glu23ValfsTer17 — a frameshift creating a premature stop. The same variant has a legacy name, 185delAG, from an older numbering system, and a database identifier, rs80357906. Three labels, one variant — HGVS is the one that travels unambiguously between laboratories.
Where reclassifications land
When a VUS is later re-evaluated against accumulated evidence, the great majority resolve toward benign rather than toward pathogenic — a reason a VUS rarely warrants pre-emptive intervention. Figures from a multicentre cohort (n=2,715 patients with a VUS).
reclassified VUS moving to LB/B
reclassified VUS moving to LP/P, clinically actionable
Common questions about results
My result is a VUS. What should I do?
On its own, a VUS should not change your screening or trigger surgery — ACMG/AMP guidance and NCCN are explicit that management is driven by your personal and family history, not by an uncertain variant. Cascade testing of relatives is generally not offered for a VUS. A genetic counsellor can explain what it means for you and whether re-contact is planned.
Why can a classification change later?
Classifications are evidence-based, and evidence accumulates. As databases grow, functional studies report, and family data link a variant to (or clear it of) disease, a VUS may be reclassified. Laboratories periodically re-evaluate and may re-issue reports — which is why staying reachable through your clinic matters.
Is 'likely pathogenic' meaningfully different from 'pathogenic'?
The labels reflect certainty — roughly 90% versus 99%. In practice, likely pathogenic and pathogenic variants are usually managed the same way clinically, while the residual uncertainty is discussed in counselling.
Why does my report show several names for one variant?
Standard HGVS notation (c.68_69delAG), a protein consequence (p.Glu23ValfsTer17), a legacy clinical name (185delAG), and a database ID (rs80357906) can all denote the same change. HGVS against a named reference transcript is the unambiguous form used between laboratories.
“A classification is a snapshot of today's evidence, not a permanent verdict. The discipline of a registry is keeping families reachable so that snapshot can be updated.”
- [1]ACMG/AMP 2015. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the ACMG and the AMP. Genet Med. 2015;17(5):405–424.↗
- [2]Cancer Medicine 2023. Makhnoon S, et al. A multicenter study of clinical impact of variant of uncertain significance reclassification in breast, ovarian and colorectal cancer susceptibility genes. Cancer Med. 2023.↗
- [3]ClinVar — BRCA1 c.68_69delAG. NM_007294.4(BRCA1):c.68_69del (p.Glu23fs), VCV000017662 — variant record and clinical interpretations.↗
- [4]JCO / ASCO 2016. Domchek SM, et al. Prospective Registry of Multiplex Testing (PROMPT): a web-based platform to assess cancer risk of genetic variants. J Clin Oncol. 2016;34(15_suppl):1518.↗
- [5]NHS Genomics Education. Variant of uncertain significance (VUS) — Knowledge Hub.↗
Keep reading before you act on a result
Understanding the label is the first step; a clinician or genetic counsellor interprets it against your own history. Our guides cover panels, BRCA-specific risk, and the vocabulary of a report.