Molecular Pathology umbrella

Molecular Pathology training for NHS biomedical scientists

Cross-disciplinary training across Genomics, NGS, PCR, molecular histology and molecular virology — aligned to the NHS Genomic Medicine Service, IBMS competency framework, and HCPC Standards of Proficiency.

Reviewed by Desmond O., HCPC-registered Biomedical Scientist, and the PathologyLabTraining editorial team

9 min read
NHS GMS aligned
ACMG 5-tier classification

What's covered

Four interlocking disciplines. Expand any item to see techniques, common pitfalls, and the QC checks that matter in UK Molecular Pathology labs.

NHS Genomic Medicine Service alignment

UK molecular pathology is increasingly delivered through the NHS GMS and its seven Genomic Laboratory Hubs. Our training reflects current Genomics England Test Directory categories, Tier 1 / Tier 2 testing workflows, and the IBMS pathway for genomic scientist registration.

The NGS pipeline

From specimen reception through MDT report. Each stage has a quality risk that the OSPE will probe.

  1. 01
    Stage
    Sample
    What happens
    EDTA blood, FFPE block, or extracted DNA/RNA arrives. Pre-analytic quality checks.
    Risk to manage
    DNA degradation in old FFPE, low yield from paucicellular samples
  2. 02
    Stage
    Extraction
    What happens
    Automated or manual nucleic acid extraction; quantification (Qubit / Nanodrop).
    Risk to manage
    Carryover contamination on automated platforms
  3. 03
    Stage
    Library prep
    What happens
    Fragmentation, end-repair, adapter ligation, barcoding for multiplexing.
    Risk to manage
    Adapter dimers, suboptimal insert size, barcode bleed
  4. 04
    Stage
    Sequencing
    What happens
    Cluster generation + sequencing-by-synthesis on Illumina (or long-read on Nanopore / PacBio).
    Risk to manage
    Cluster density too high → low Q30; reagent expiry
  5. 05
    Stage
    Bioinformatics
    What happens
    Trim, align, call variants, annotate against population databases (gnomAD, ClinVar).
    Risk to manage
    Reference assembly mismatch (GRCh37 vs GRCh38)
  6. 06
    Stage
    Interpretation
    What happens
    ACMG 5-tier classification, evidence assembly, clinical relevance.
    Risk to manage
    VUS reporting fatigue; over-call of incidental findings
  7. 07
    Stage
    MDT report
    What happens
    Variant report signed off and discussed at Genomic MDT with clinicians.
    Risk to manage
    Misalignment between phenotype and interpretation if MDT skipped

ACMG 5-tier classification — worked example

A genuine reasoning walkthrough: take a single variant from VCF entry to a defensible classification.

How to approach it

This example is hypothetical and intended for teaching only. Always use ClinVar, the current ACMG/AMP guidance, and your local Genomic MDT for actual variant classification.

Step 1: identify the variant type

A nonsense (stop-gain) variant in BRCA2 — a tumour suppressor gene with a well-established loss-of-function mechanism — is highly likely to be deleterious because the transcript typically undergoes nonsense-mediated decay.

Step 2: apply ACMG criteria

  • PVS1 (very strong pathogenic) — null variant in a gene where loss-of-function is the known disease mechanism. PVS1 strength may be modulated using the ClinGen SVI 2018 PVS1 decision tree (e.g. downgraded if the variant is in the last exon and escapes NMD).
  • PM2_supporting (supporting pathogenic) — absent or extremely rare in gnomAD. Per the ClinGen 2020 update, PM2 is generally applied at supporting strength rather than moderate.

Step 3: combine evidence per ACMG rules

The ACGS guidelines (2026, version 3) use the ClinGen points system (Very Strong = 8, Strong = 4, Moderate = 2, Supporting = 1; Likely Pathogenic 6 to 9, Pathogenic 10 or more). PVS1 (8) + PM2_Supporting (1) = 9 points, so with only this evidence the classification is Likely Pathogenic. A ClinVar entry is not a criterion in its own right: ClinGen recommended discontinuing PP5 in 2018, so any published evidence must be reviewed and applied under its own criterion.

Step 4: clinical action and reporting

  • Report only after Genomic MDT consensus.
  • Likely pathogenic variants are used for clinical decision-making in the same way as pathogenic ones, so cascade testing of first-degree relatives is offered via clinical genetics.
  • Patient counselled on enhanced surveillance and risk-reducing options (per NICE / regional pathway).

What OSPE markers look for

  1. You explicitly named which ACMG criteria apply (not vague reasoning).
  2. You recognised the LoF mechanism for BRCA2 specifically — and the limits of PVS1 (e.g. NMD escape).
  3. You applied the current PM2 strength (supporting, not moderate) per ClinGen 2020, and added the points correctly to reach Likely Pathogenic.
  4. You linked the variant call to the clinical action — MDT, cascade testing, surveillance.
Maps to
ACMG/AMP 2015 guideline (Richards et al.)
ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2026 (version 3)
ClinGen Sequence Variant Interpretation Working Group updates
IBMS Genomics Specialist Portfolio

HER2 IHC quick reference

ASCO/CAP scoring used by UK histopathology labs. HER2-low (IHC 1+, or 2+ with a negative ISH result) is not an ASCO/CAP interpretive category, but the exact score must be reported because metastatic HER2-low breast cancer may be considered for trastuzumab deruxtecan. ER and PR follow Allred scoring (different scale — keep them separate).

Staining patternInterpretationReflex action
0
No staining observed, OR membrane staining that is incomplete and faint/barely perceptible within ≤ 10% of tumour cells		HER2 negativeNo reflex ISH
1+
Incomplete membrane staining, faint/barely perceptible, in > 10% of tumour cells		HER2 negativeNo reflex ISH
2+
Weak-to-moderate complete membrane staining in > 10% of tumour cells		EquivocalReflex to ISH / FISH for definitive call
3+
Circumferential membrane staining that is complete, intense, and within > 10% of tumour cells		HER2 positiveEligible for HER2-directed therapy

NHS GMS Test Directory — R-codes vs M-codes

The Test Directory is organised by eligibility codes rather than tier numbers — R-codes for rare disease testing and M-codes for cancer (somatic) testing. The current Directory is maintained by NHS England.

ScopeCode structureExample codesReferral pathway
R-codes
Rare and inherited disease testing.		Each "R" code defines an eligibility statement and the testing technology / panel approved for it.Inherited breast and ovarian cancer panels, familial hypercholesterolaemia, early-onset epilepsy panels, neurodevelopmental rare-disease WGS.Eligibility-driven — clinician confirms the patient meets the R-code criteria before request.
M-codes
Cancer (somatic) genomic testing.		Each "M" code defines a tumour-type / actionability use case and the approved testing approach.Solid-tumour and haematological malignancy panels, e.g. acute myeloid leukaemia profiling, solid-tumour large panel.Clinical eligibility per Test Directory; complex or non-standard requests via Genomic MDT discussion.

Examples are illustrative. See the live NHS National Genomic Test Directory for current codes and eligibility criteria.

Career pathway in Molecular Pathology

Two routes lead into NHS molecular pathology: the IBMS Specialist Diploma (most common) and the STP Genomic Sciences track.

  1. I

    BSc Biomedical Science

    3-4 years

    IBMS-accredited degree — foundation for HCPC pathway.

    Outcome: graduate-entry eligible

  2. II

    IBMS Genomics Specialist Diploma

    ~18 months

    Specialist Portfolio in Genomics for qualified BMS staff working in NHS GMS labs.

    Outcome: Specialist BMS (Genomics)

  3. III

    STP Genomic Sciences (alternative route)

    3 years

    NHS Scientist Training Programme — 3-year work-based MSc with rotations.

    Outcome: Clinical Scientist (Genomics)

  4. IV

    Clinical Scientist / Consultant

    Continuous

    Independent variant interpretation, MDT leadership, service development.

    Outcome: Band 8 leadership / Consultant Clinical Scientist

Molecular Pathology glossary

ACMG— American College of Medical Genetics and Genomics
Co-author, with AMP, of the 5-tier variant classification guidance (Pathogenic / Likely pathogenic / VUS / Likely benign / Benign). UK genomic labs apply it through the ACGS Best Practice Guidelines for Variant Classification.
CNV— Copy Number Variation
Gain or loss of DNA segments. Detected by NGS read-depth or by MLPA / array CGH depending on size.
FISH— Fluorescence In Situ Hybridisation
Cytogenetic technique used to detect specific DNA sequences on chromosomes — e.g. HER2 gene amplification.
indel
Insertion or deletion variant. Small (1-50 bp) indels are detected from NGS read alignment; large indels often need orthogonal methods.
ISH— In Situ Hybridisation
Technique for localising specific nucleic acid sequences within a tissue section. ISH is a general term that includes FISH and CISH.
MAF— Minor Allele Frequency
The frequency of the less common allele at a locus in a population. Used with ACMG criteria — high MAF in gnomAD usually indicates benign.
MDT— Multidisciplinary Team
Genomic MDT brings together clinical scientists, geneticists and referring clinicians to agree variant significance before reporting.
NGS— Next-Generation Sequencing
Parallel sequencing technologies (Illumina, Ion Torrent, Oxford Nanopore) that allow massive throughput compared with Sanger sequencing.
panel
A gene-set assay — typically 5-200 genes — chosen for relevance to a specific clinical question (e.g. inherited cancer panel).
VUS— Variant of Uncertain Significance
ACMG tier 3. Insufficient evidence to call pathogenic or benign. Usually NOT actioned clinically until reclassified.
WES— Whole Exome Sequencing
Sequencing of all protein-coding regions (~1% of the genome) — covers ~85% of known disease-causing variants at lower cost than WGS.
WGS— Whole Genome Sequencing
Sequencing of all coding and non-coding DNA. Used for rare disease diagnostics and 100,000 Genomes-style research in NHS GMS.

Frequently asked questions

What does Molecular Pathology training cover?
Genomics (NGS, variant interpretation, ACMG, NHS GMS workflows), PCR and molecular diagnostics, molecular histology (IHC, ISH, FISH, HER2/ER/PR scoring), and molecular virology (viral load, HIV/HCV/HBV testing, antiviral resistance genotyping).
Is the training aligned to NHS Genomic Medicine Service?
Yes. Training reflects the seven NHS GMS Genomic Laboratory Hubs, current Genomics England Test Directory categories, and Tier 1 / Tier 2 testing workflows.
Does it support the IBMS Genomics Specialist Diploma route?
Yes. The Molecular Pathology training maps to the IBMS Genomics Specialist Portfolio and supports the BMS career pathway into genomic science.
Is it relevant for Clinical Scientist (Genomics) STP applicants?
Yes — content covers the Scientist Training Programme (STP) Genomic Sciences track preparation, including variant interpretation, bioinformatics pipelines, and MDT reporting practice.
Does the training cover molecular accreditation requirements?
Yes — ISO 15189:2022 molecular section, UKAS accreditation framework, GenQA EQA scheme integration, contamination control, and method validation specifically for molecular assays.

Build NHS molecular pathology expertise

From PCR fundamentals to NGS variant interpretation — training that mirrors NHS Genomic Medicine Service practice, with interview readiness built in.

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