Inherited line
A body-wide variant may matter for relatives: BRCA1/2, MMR, APC, TP53, RET and others.
Specimen: usually blood/salivaONCOLOGY / MODULE 0.8
A mutation is not a prescription. Sometimes it changes the treatment conversation.
A practical atlas of inherited risk, tumour biomarkers and molecular-test quality metrics. No doses and no automated decisions.
RUSSIAN CARE ROUTE
Where to seek molecular oncology testing in Russia.
When cancer has been diagnosed, the need and scope of testing should first be discussed with the treating oncologist. As a specialist Russian route, the project recommends considering the molecular-genetic methods group and the Laboratory of Molecular Oncology at the N.N. Petrov NMRC of Oncology.
This is an editorial route—not a guarantee, referral, paid placement or claim that this is the only suitable laboratory. Confirm availability, documents, price and test menu with the centre.
00 / EDITORIAL CONTACT
Suggest a test or ask a question.
The form uploads nothing to the website: after validation, it opens a prepared draft in your email app. Do not send a diagnosis, test result, genetic variant, medical record or another person’s data.
01Suggest a test+
02Ask a question+
The draft is addressed to help@mika.help. You can review and edit it in your email app before sending.
CLINICAL GATEFor clinician discussion only
The matrix does not capture the complete diagnosis, stage, morphology, prior lines, contraindications or country-specific authorisation. It neither prescribes nor stops treatment.
Check an exact relationship →Tumour genome
Acquired drivers, resistance, MSI/TMB/HRD and fusions inform specific treatment discussions.
Specimen: tissue or ctDNATreatment toxicity
Germline pharmacogenetics, such as DPYD, estimates adverse-reaction risk rather than tumour sensitivity.
Decision: clinician + monitoring01 / BIOMARKER → DECISION
Not a drug list. A map of verifiable clinical relationships.
The map currently contains 43 clinical relationships: driver variants, fusions, signatures, inherited and pharmacogenetic findings, plus several essential protein and epigenetic biomarkers. It is expanded but not exhaustive. Open a row to see the assay, report fields, clinical role and main limitation.
43relations
01Non-small-cell lung cancerEGFRRegulator-backed predictive biomarker+
Finding
Activating mutation, especially exon 19 deletion or p.L858R; other variants require separate interpretation.
Specimen and assay
Tumour tissue; plasma ctDNA when tissue is unavailable or speed is critical. Validated PCR/NGS with a declared variant list and limit of detection.
What the report needs
HGVS variant, exon, VAF, coverage/quality, specimen type and assay sensitivity.
What a clinician may discuss
EGFR-directed therapy in defined stages and lines; the exact drug follows the current label and clinical context.
Critical limitation
Negative plasma does not exclude a mutation: reflex tissue testing is needed when feasible. Exon 20 and resistance variants are separate scenarios.
02Non-small-cell lung cancerALK fusionHigh for a confirmed ALK fusion+
Finding
A functional ALK fusion, generally retaining the kinase domain.
Specimen and assay
Tissue is preferred; cytology is acceptable after validation. Validated ALK IHC, FISH or RNA/DNA NGS in a concordant algorithm; RNA NGS helps characterise an expressed fusion.
What the report needs
Fusion name (for example, EML4::ALK); partner genes and exon/breakpoint details when resolved by the assay; reading frame, retained kinase domain, supporting reads, QC and any confirmation requirement.
What a clinician may discuss
ALK-directed therapy in a defined stage and line.
Critical limitation
An unusual NGS rearrangement without expression evidence may require RNA confirmation; methods have different failure modes.
03Non-small-cell lung cancerKRAS p.G12CHigh for the exact allele+
Finding
The specific activating KRAS p.G12C substitution; other KRAS alleles belong to different clinical relationships.
Specimen and assay
Tumour tissue; plasma is acceptable for some validated assays. Validated PCR or DNA NGS with exact allele identification.
What the report needs
HGVS, VAF, tumour fraction, LoD, QC and relevant co-drivers.
What a clinician may discuss
A KRAS G12C-directed strategy within the relevant line and label.
Critical limitation
A p.G12D, p.G12V or generic ‘KRAS mutation’ result is not positive for this relationship.
04Non-small-cell lung cancerROS1 fusionHigh for a confirmed fusion+
Finding
An oncogenic ROS1 fusion retaining the kinase domain.
Specimen and assay
Tumour tissue; validated plasma may be used with adequate tumour fraction. RNA NGS is preferred for broad detection; ROS1 IHC may screen with molecular confirmation.
What the report needs
Fusion name, partner/breakpoints when resolved, frame, kinase domain, supporting reads and QC.
What a clinician may discuss
ROS1-directed therapy in a defined stage and line.
Critical limitation
ROS1 IHC is not a definitive positive result in every algorithm; an unusual fusion requires structural and RNA review.
05Non-small-cell lung cancerRET fusionHigh for a confirmed fusion+
Finding
An oncogenic RET fusion; a RET mutation, amplification and expression are not equivalents.
Specimen and assay
Tumour tissue; validated plasma is acceptable in a defined setting. RNA NGS is preferred for expressed fusions; DNA NGS may require RNA reflex testing.
What the report needs
Fusion name, partner and breakpoints when resolved, frame, kinase domain, supporting reads and QC.
What a clinician may discuss
Selective RET-directed therapy within the exact indication.
Critical limitation
A rare DNA rearrangement without confirmed expression may be non-informative.
06Non-small-cell lung cancerNTRK1/2/3 fusionHigh for a confirmed functional fusion+
Finding
A functional NTRK fusion—not a point variant or TRK expression alone.
Specimen and assay
Tumour tissue. RNA NGS is preferred; pan-TRK IHC may be used as a screen with molecular confirmation.
What the report needs
Exact fusion, frame, retained kinase domain, supporting reads, QC and confirmation of an unusual finding.
What a clinician may discuss
TRK-directed therapy in an established organ-specific or tumour-agnostic setting.
Critical limitation
Rarity increases the cost of false positives; RNA quality is critical.
07Non-small-cell lung cancerMET exon 14 skippingHigh for confirmed skipping+
Finding
A variant causing MET exon 14 skipping or a confirmed RNA transcript showing skipping.
Specimen and assay
Tumour tissue; validated plasma may be used. Splice-aware DNA NGS and/or RNA NGS; design must cover diverse intron/exon boundaries.
What the report needs
HGVS and predicted splice effect, RNA confirmation when performed, VAF, boundary coverage, QC and LoD.
What a clinician may discuss
MET-directed therapy in a defined line.
Critical limitation
MET amplification and MET exon 14 skipping are different biomarkers; not every intronic variant disrupts splicing.
08Non-small-cell lung cancerBRAF p.V600EHigh for the exact allele+
Finding
The specific activating BRAF p.V600E mutation.
Specimen and assay
Tumour tissue or validated plasma. PCR or DNA NGS that precisely distinguishes V600E from other BRAF classes.
What the report needs
HGVS, VAF, tumour fraction, sensitivity, QC and relevant co-drivers.
What a clinician may discuss
A BRAF/MEK-directed combination in the relevant stage and line.
Critical limitation
Non-V600 BRAF variants have different biology; the melanoma pathway cannot be transferred without checking the indication.
09Non-small-cell lung cancerERBB2 / HER2 activating mutationHigh for defined activating mutations+
Finding
An activating ERBB2 mutation, including defined exon 20 insertions; this is not the same as HER2 IHC or amplification.
Specimen and assay
Tumour tissue; validated plasma may be used. DNA NGS with complete coverage of relevant exons and exact allele annotation.
What the report needs
HGVS, exon, VAF, functional class, coverage, QC and separate amplification/IHC status when assessed.
What a clinician may discuss
A HER2-directed strategy for HER2-mutant NSCLC within the exact indication.
Critical limitation
An ERBB2 VUS, amplification and HER2-low are not interchangeable positive results.
10Breast cancer and selected GI cancersERBB2 / HER2Standard predictive biomarker+
Finding
ERBB2 amplification and/or HER2 protein overexpression; HER2-low is a separate protein category, not a ‘weak mutation’.
Specimen and assay
Fixed tumour tissue with controlled preanalytics. IHC with reflex ISH/FISH under a validated algorithm; NGS-CNV does not always replace the standard companion assay.
What the report needs
IHC score, ISH ratio/copy number, heterogeneity and specimen adequacy.
What a clinician may discuss
HER2-directed therapy; choice depends on organ, stage, prior lines and expression category.
Critical limitation
ERBB2 amplification, activating ERBB2 mutation and HER2-low are not interchangeable biomarkers.
11HR-positive HER2-negative advanced breast cancerPIK3CA · AKT1 · PTEN · ESR1Regulator-backed for defined variants+
Finding
An exact PIK3CA, AKT1, PTEN or ESR1 alteration covered by a validated assay for a specific indication; eligible alterations differ by medicine and jurisdiction.
Specimen and assay
Tissue and/or plasma ctDNA; plasma can capture acquired ESR1 clones. Validated NGS/PCR; the covered variant list must match the clinical question.
What the report needs
Exact variant, VAF, timing relative to treatment, negative result and LoD.
What a clinician may discuss
Selection of the relevant targeted or endocrine approach after receptor status and prior therapy are considered.
Critical limitation
Not every PI3K–AKT pathway alteration is one positive result; approvals differ.
12Metastatic colorectal cancerKRAS · NRASHigh: exclusion/selection biomarker+
Finding
Absence of activating mutations in clinically relevant KRAS/NRAS regions is a negative predictive biomarker.
Specimen and assay
Tumour tissue; plasma can be used in a validated setting. Extended RAS testing covering exons 2, 3 and 4 of both genes.
What the report needs
Not merely ‘wild type’: report covered exons, sensitivity, tumour fraction and QC.
What a clinician may discuss
An anti-EGFR approach may be discussed for RAS wild type; primary tumour sidedness and other factors remain material.
Critical limitation
Wild type means ‘not detected within this assay’, not absence of every resistance mechanism.
13Colorectal cancer, melanoma and selected solid tumoursBRAF p.V600EHigh, but strongly tumour-specific+
Finding
The specific activating p.V600E substitution; other BRAF classes have different biological and clinical meaning.
Specimen and assay
Tumour tissue or validated plasma. PCR or NGS that correctly distinguishes V600E from other variants.
What the report needs
HGVS, VAF and QC; in colorectal cancer include MMR/MSI and clinical context.
What a clinician may discuss
A BRAF-directed combination that differs by tumour type; the melanoma strategy is not copied into CRC.
Critical limitation
The same mutation does not guarantee the same sensitivity across organs.
14Colorectal, endometrial and other solid tumoursMSI-H / dMMRHigh: tumour-specific and tumour-agnostic indications+
Finding
High microsatellite instability or deficiency of mismatch-repair proteins MLH1/MSH2/MSH6/PMS2.
Specimen and assay
Tumour tissue; patient blood can serve as a normal control for some methods. MMR IHC, PCR-MSI or validated NGS-MSI; methods answer related but non-identical questions.
What the report needs
Method, result for each protein or microsatellite locus, internal controls and quality; concordance only when multiple methods were used; indications for germline follow-up.
What a clinician may discuss
Immunotherapy in defined stages/lines; simultaneously assess the possibility of Lynch syndrome.
Critical limitation
Therapeutic dMMR/MSI-H status is not a Lynch-syndrome diagnosis; sporadic mechanisms exist.
15Ovarian cancer; also selected breast, pancreatic and prostate cancersBRCA1 · BRCA2 · HRD/HRRHigh for defined assays and indications+
Finding
A pathogenic tumour or germline BRCA1/2 variant; HRD is a separate composite result from a validated assay.
Specimen and assay
Tumour plus a separate germline specimen when indicated. NGS with CNV for BRCA1/2; a validated HRD assay with a stated algorithm and threshold.
What the report needs
Exact variant and classification; origin only when somatic or germline status has been separately established. For a composite HRD assay: assay name, algorithm version, components, numeric result, threshold and QC.
What a clinician may discuss
A PARP-directed strategy within the exact organ, stage, prior response and regulatory label.
Critical limitation
‘Any HRR mutation’ and ‘HRD-positive’ are not interchangeable; a VUS is not a positive BRCA biomarker.
16Solid tumours across organsNTRK1 · NTRK2 · NTRK3High for confirmed functional fusions+
Finding
An oncogenic NTRK fusion—not a point variant or merely elevated TRK expression.
Specimen and assay
Tumour tissue. RNA-NGS is preferred for broad detection; pan-TRK IHC can screen with molecular confirmation.
What the report needs
Exact fusion name; partners and breakpoints when resolved by the assay; reading frame, RNA expression when assessed, supporting reads, QC and the confirmation approach for an unusual finding.
What a clinician may discuss
A TRK inhibitor in a tumour-agnostic indication when appropriate alternatives are lacking, subject to the label.
Critical limitation
Rarity increases the cost of false positives; unusual fusions require confirmation.
17Intrahepatic cholangiocarcinomaFGFR2 · IDH1High for defined alterations+
Finding
An FGFR2 fusion/rearrangement or a defined IDH1 mutation.
Specimen and assay
Tumour tissue; plasma in a validated context. RNA NGS improves detection of expressed FGFR2 fusions; DNA NGS detects IDH1 substitutions and can detect some FGFR2 rearrangements. The combination depends on the validated assay design.
What the report needs
For FGFR2 report partner and frame; for IDH1 report exact codon/variant; include QC and VAF.
What a clinician may discuss
FGFR- or IDH1-directed therapy after considering line and current authorisation.
Critical limitation
Not every FGFR2 alteration is sensitive; resistance and subsequent mutations require separate review.
18Any cancer where fluoropyrimidines are consideredDPYD / DPDClinical pharmacogenetics+
Finding
A reduced-function germline genotype and/or DPD-deficiency phenotype.
Specimen and assay
Blood/buccal specimen for genotype; plasma for phenotyping under a local protocol. Validated clinically relevant variant panel and/or phenotyping; coverage differs across populations.
What the report needs
Alleles, activity score/phenotype, panel limitations and a clinician-facing recommendation without self-directed dose changes.
What a clinician may discuss
A clinician may alter the starting strategy or select an alternative; ongoing monitoring remains mandatory.
Critical limitation
A normal limited-panel result does not exclude severe toxicity; this is not a tumour-response biomarker.
19Non-small-cell lung cancerEGFR exon 20 insertionHigh for defined variants and indications+
Finding
An EGFR exon 20 insertion with the exact variant reported; this is a separate clinical class from classic sensitising variants.
Specimen and assay
Tumour tissue; validated plasma ctDNA is acceptable in defined settings. NGS or a validated PCR assay able to detect diverse exon 20 insertions.
What the report needs
HGVS, insertion length and position, VAF, exon coverage, LoD and specimen type.
What a clinician may discuss
A dedicated EGFR-directed strategy within the exact indication and current authorisation.
Critical limitation
The result must not be interpreted using the exon 19 deletion or p.L858R pathway.
20Non-small-cell lung cancerPD-L1 / TPSStandard protein predictive biomarker+
Finding
The proportion of tumour cells with membranous PD-L1 expression on a validated IHC assay; this is a protein, not a genetic, biomarker.
Specimen and assay
Representative tumour tissue or validated cytology material. A companion or clinically validated IHC clone with TPS scoring.
What the report needs
Antibody clone, platform, TPS percentage, viable-cell count, heterogeneity and QC.
What a clinician may discuss
An immunotherapy strategy considering stage, oncogenic drivers, regimen and the indication-specific threshold.
Critical limitation
PD-L1 thresholds and meaning depend on medicine and regimen; a negative result does not exclude every immunotherapy option.
21Advanced breast cancerHER2-low / HER2-ultralowClinically actionable IHC category+
Finding
Low or very low HER2 membrane expression under defined IHC criteria without HER2-positive status; this is a protein category, not a mutation.
Specimen and assay
Current representative tumour tissue, preferably from a clinically relevant lesion. Validated HER2 IHC with reflex ISH for borderline categories under the current algorithm.
What the report needs
IHC score, staining intensity and completeness, cell proportion, ISH when needed, specimen and date.
What a clinician may discuss
A HER2-directed antibody-drug conjugate in a defined line and expression category.
Critical limitation
The category is sensitive to preanalytics, observer variation and expression changes across lesions and time.
22HER2-negative breast cancer in a clinically indicated settinggBRCA1 · gBRCA2High: therapy plus inherited risk+
Finding
A pathogenic or likely pathogenic germline BRCA1/2 variant; a VUS is not a positive result.
Specimen and assay
A separate blood/saliva specimen confirming germline origin. NGS of coding and splice regions plus large deletion/duplication analysis.
What the report needs
HGVS, ACMG/AMP classification, transcript, method, CNV coverage and genetic-counselling recommendation.
What a clinician may discuss
A systemic strategy in a defined stage; separately, inherited risk and family follow-up.
Critical limitation
A tumour BRCA variant does not prove germline origin; a negative test does not exclude all inherited risk.
23Triple-negative breast cancerPD-L1 / CPSHigh in a defined indication+
Finding
PD-L1 expression with CPS calculated using the required validated IHC assay; this is a protein biomarker.
Specimen and assay
Representative tumour tissue with sufficient viable cells. Indication-specific IHC clone, platform and CPS algorithm.
What the report needs
Clone, platform, CPS, adequacy, internal controls, tested lesion and date.
What a clinician may discuss
Immunotherapy in the specific stage and combination when the defined threshold is met.
Critical limitation
A lung-cancer TPS threshold or another clone’s result cannot be transferred without validated interchangeability.
24Metastatic colorectal cancerERBB2 / HER2 amplificationHigh in a selected population+
Finding
High-level ERBB2 amplification and/or HER2-positive status under a validated algorithm in the relevant molecular context.
Specimen and assay
Tumour tissue; plasma can be complementary in a validated setting. IHC/ISH and/or validated NGS-CNV with tumour-specific thresholds.
What the report needs
IHC/ISH parameters or copy number, tumour purity, heterogeneity, RAS/BRAF context and QC.
What a clinician may discuss
A HER2-directed combination after prior therapy and the exact indication are considered.
Critical limitation
Breast-cancer HER2 positivity criteria cannot be transferred automatically to CRC.
25Metastatic colorectal cancerKRAS p.G12CRegulator-backed for the exact allele+
Finding
The specific KRAS p.G12C substitution; other KRAS variants are not equivalent.
Specimen and assay
Tumour tissue or validated plasma ctDNA. PCR or NGS with adequate sensitivity and exact allele identification.
What the report needs
HGVS, VAF, LoD, tumour fraction and relevant co-drivers.
What a clinician may discuss
A KRAS G12C-directed combination specific to CRC and treatment line.
Critical limitation
A monotherapy approach from another tumour must not be mechanically transferred to CRC.
26Gastric or gastro-oesophageal junction adenocarcinomaERBB2 / HER2Standard predictive biomarker+
Finding
HER2 overexpression and/or amplification under the gastro-oesophageal algorithm.
Specimen and assay
Multiple representative tumour fragments because heterogeneity is common. IHC with reflex ISH under organ-specific criteria.
What the report needs
IHC score, staining pattern, ISH, number of blocks/fragments assessed and heterogeneity.
What a clinician may discuss
A HER2-directed strategy in the relevant line; repeat testing may be needed as the context changes.
Critical limitation
Scoring differs from breast cancer; a negative small biopsy can be unrepresentative.
27HER2-negative gastric or gastro-oesophageal junction adenocarcinomaCLDN18.2High for a validated IHC threshold+
Finding
CLDN18.2 membrane expression above the indication-specific threshold; this is a protein IHC biomarker, not a CLDN18 gene variant.
Specimen and assay
Representative tumour tissue. The required validated IHC assay with a defined scoring algorithm.
What the report needs
Clone/kit, platform, cell percentage and membrane-staining intensity, threshold, adequacy and QC.
What a clinician may discuss
CLDN18.2-directed therapy in the exact line and combination.
Critical limitation
Positivity is not established by RNA expression or a CLDN18 variant without a validated clinical relationship.
28Pancreatic adenocarcinomagBRCA1 · gBRCA2 · PALB2High for gBRCA in a defined setting+
Finding
A pathogenic germline BRCA1/2 variant; PALB2 is clinically important but must not be automatically equated with every BRCA companion relationship.
Specimen and assay
Blood/saliva for germline testing; tumour tissue may add context. NGS plus CNV analysis with confirmation of a clinically significant finding.
What the report needs
Exact variant, class, origin, CNV coverage, limitations and genetic-counselling route.
What a clinician may discuss
Platinum sensitivity and/or a maintenance targeted strategy in a defined scenario; family risk is addressed separately.
Critical limitation
Somatic and germline variants have different family implications; a VUS does not determine treatment.
29Gastrointestinal stromal tumourKIT · PDGFRAHigh and allele-specific+
Finding
A driver KIT or PDGFRA variant with the exact exon and allele; specific variants predict sensitivity or primary resistance.
Specimen and assay
Tumour tissue with morphologically confirmed GIST. DNA sequencing of relevant exons; broader testing for KIT/PDGFRA wild-type disease when clinically indicated.
What the report needs
Gene, exon, HGVS, VAF, coverage, wild-type boundaries and secondary resistance variants at relapse.
What a clinician may discuss
Selection and sequencing of inhibitor classes based on the exact primary and secondary variant.
Critical limitation
KIT-positive IHC does not replace genotyping for therapeutic selection.
30Endometrial cancerPOLE · MMR · p53 · NSMPDiagnostic and prognostic classification+
Finding
An integrated molecular class: POLEmut, MMRd, p53abn or NSMP, with rules for resolving multiple classifiers.
Specimen and assay
Tumour tissue linked to the morphology report. Sequencing for pathogenic POLE hotspot variants plus MMR and p53 IHC under a validated algorithm.
What the report needs
POLE variant and pathogenicity, each MMR protein, p53 pattern, final class, morphology and applied hierarchy.
What a clinician may discuss
Prognosis, staging and adjuvant-strategy intensity; MMRd can also have predictive and inherited implications.
Critical limitation
Not every POLE mutation creates a POLEmut class; TP53 sequencing and p53 IHC are not fully interchangeable.
31Platinum-resistant epithelial ovarian cancer in a defined settingFRα / FOLR1High for a validated IHC assay+
Finding
High folate receptor alpha membrane expression above an indication-specific IHC threshold; this is a protein biomarker.
Specimen and assay
Archived or fresh representative tumour tissue under the validated assay requirements. A companion IHC assay with defined intensity and positive-cell proportion.
What the report needs
Kit/clone, platform, percentage of cells at the required intensity, threshold, specimen and QC.
What a clinician may discuss
An FRα-directed antibody-drug conjugate within the exact indication and prior-line requirements.
Critical limitation
FOLR1 amplification or RNA expression does not replace the required companion IHC assay.
32Metastatic castration-resistant prostate cancerBRCA1 · BRCA2 · HRR panelHigh for defined genes and regimens+
Finding
A pathogenic alteration in a specific homologous-recombination repair gene; eligible genes depend on medicine, assay and jurisdiction.
Specimen and assay
Tumour tissue and/or validated plasma; a separate germline specimen when indicated. DNA NGS with SNV/indel/CNV; plasma interpretation must consider tumour fraction and clonal haematopoiesis.
What the report needs
Gene, exact variant, class, VAF/copy number, biallelic status if established, specimen type, QC and possible germline origin.
What a clinician may discuss
A PARP-directed strategy matched to the exact gene, combination and line.
Critical limitation
HRR genes are not interchangeable; benefit differs by gene, and a VUS is not a positive result.
33Advanced prostate cancerMSI-H / dMMRHigh for confirmed MSI-H/dMMR+
Finding
MSI-H or MMR deficiency established by a validated method.
Specimen and assay
Tumour tissue; plasma is acceptable only with a validated MSI assay and adequate tumour fraction. MMR IHC, PCR-MSI or NGS-MSI with a validated threshold.
What the report needs
Method, numeric/categorical result, quality controls, tumour fraction and indications for germline follow-up.
What a clinician may discuss
Immunotherapy in a defined setting and evaluation of inherited cause when indicated.
Critical limitation
Rarity requires strict QC; negative plasma at low tumour fraction does not exclude MSI-H.
34Locally advanced or metastatic urothelial cancerFGFR3 · FGFR2High for defined alterations+
Finding
A defined activating FGFR3 mutation or eligible FGFR2/3 fusion covered by a validated companion relationship.
Specimen and assay
Tumour tissue; validated plasma may complement testing. DNA/RNA NGS or an authorised targeted assay with a declared variant and fusion list.
What the report needs
Exact variant/fusion, coverage, VAF or supporting reads, QC and match to the clinically eligible list.
What a clinician may discuss
FGFR-directed therapy in a defined line with required monitoring.
Critical limitation
Not every FGFR alteration is activating or sensitive; amplification is not equivalent to an eligible mutation/fusion.
35Unresectable or metastatic melanomaBRAF p.V600Standard predictive biomarker+
Finding
A BRAF codon V600 mutation with the exact allele, particularly V600E or V600K.
Specimen and assay
Tumour tissue. Validated PCR or NGS distinguishing V600 alleles with a controlled LoD.
What the report needs
HGVS, allele, VAF, tumour fraction, sensitivity and QC.
What a clinician may discuss
A combined BRAF/MEK-directed strategy or an alternative systemic approach according to clinical context.
Critical limitation
Non-V600 BRAF variants must not automatically follow the V600 pathway; organ context matters.
36Selected mucosal, acral and chronic sun-damaged melanomasKITModerate, allele- and subtype-specific+
Finding
An activating KIT mutation in a sensitive functional region; amplification and rare VUS have different meaning.
Specimen and assay
Tumour tissue. DNA NGS of relevant exons with exact allele annotation.
What the report needs
Gene, exon, HGVS, VAF, functional class, allele-specific evidence and QC.
What a clinician may discuss
KIT-directed therapy in a carefully selected case or a clinical trial.
Critical limitation
Evidence is weaker and more allele-specific than for BRAF V600; KIT IHC does not replace genotype.
37Adult-type diffuse gliomaIDH1 · IDH2 · 1p/19qCore diagnostic classification+
Finding
IDH mutation status and whole-arm 1p/19q codeletion for the integrated diagnosis.
Specimen and assay
Tumour tissue with morphology assessment. IDH1 R132H IHC with reflex sequencing when indicated; 1p/19q testing must distinguish whole-arm codeletion from focal losses.
What the report needs
IDH variant, 1p/19q method, integrated diagnosis, age/morphology, QC and additional required markers.
What a clinician may discuss
Tumour classification, prognosis and organ-specific strategy; IDH-directed therapy in selected settings.
Critical limitation
A focal 1p or 19q loss is not whole-arm codeletion; molecular findings are integrated with morphology.
38Diffuse glioma, especially IDH-wild-type glioblastomaMGMT promoter methylationPrognostic and predictive marker+
Finding
MGMT promoter methylation associated with reduced repair-enzyme expression; this is an epigenetic, not sequence, alteration.
Specimen and assay
Tumour tissue with adequate tumour fraction. A validated quantitative or semi-quantitative methylation-specific assay with a defined grey zone.
What the report needs
Method, CpG sites, numeric result, threshold/grey zone, tumour fraction and QC.
What a clinician may discuss
Prognosis and expected benefit from alkylating therapy in the context of age and the overall plan.
Critical limitation
Thresholds across methods are not interchangeable; the result is neither a standalone prescription nor contraindication.
39Selected gliomas and glioneuronal tumoursBRAF p.V600E · BRAF fusionHigh for BRAF V600E in selected tumours+
Finding
The exact BRAF alteration class: p.V600E or an activating fusion; these mechanisms must not be merged.
Specimen and assay
Tumour tissue. DNA NGS for variants and RNA NGS for fusions; V600E IHC can screen in a validated algorithm.
What the report needs
HGVS or fusion name, frame/kinase domain, VAF/supporting reads, diagnosis and QC.
What a clinician may discuss
A BRAF/MEK-directed strategy for V600E in a defined setting; fusions require a different approach.
Critical limitation
Targeted-therapy evidence in CNS tumours must not be imported from melanoma without organ- and age-specific assessment.
40Selected advanced solid tumoursTMB-highRegulatory relationship with major limitations+
Finding
Somatic mutations per megabase above the validated assay- and indication-specific threshold.
Specimen and assay
Tumour tissue with adequate tumour fraction; plasma TMB is a separate metric. A validated broad DNA panel with defined territory, filters, germline handling and calibration.
What the report needs
Numeric TMB, units, assay/version, threshold, tumour fraction, MSI, QC and excluded variant classes.
What a clinician may discuss
Immunotherapy in a narrow tumour-agnostic or organ-specific setting after alternatives are assessed.
Critical limitation
TMB is not harmonised across platforms; one threshold does not predict benefit equally across tumours.
41Solid tumours with a RET fusionRET fusionHigh for a confirmed fusion+
Finding
An oncogenic RET fusion retaining the kinase domain; an activating RET mutation is a different biological relationship.
Specimen and assay
Tumour tissue; plasma is acceptable for a validated assay. RNA NGS is preferred for expressed fusions; DNA NGS may require RNA reflex testing.
What the report needs
Fusion name, partner and breakpoints when resolved, frame, kinase domain, supporting reads and QC.
What a clinician may discuss
RET-directed therapy in a defined tumour-agnostic or organ-specific indication.
Critical limitation
RET amplification, a VUS or elevated expression is not equivalent to a confirmed functional fusion.
42Selected solid tumours with BRAF p.V600EBRAF p.V600EHigh, with organ-specific exclusions+
Finding
The exact activating p.V600E substitution in a tumour covered by the relevant clinical relationship.
Specimen and assay
Tumour tissue or validated plasma. PCR/NGS with exact allele discrimination and adequate LoD.
What the report needs
HGVS, VAF, tumour fraction, diagnosis, QC and exclusions from the tumour-agnostic indication.
What a clinician may discuss
A BRAF/MEK-directed combination in an established tumour-agnostic or organ-specific setting.
Critical limitation
Some tumours require a different combination or are excluded; non-V600 variants are outside this relationship.
43Haematologic malignancies and other conditions using thiopurinesTPMT · NUDT15Clinical pharmacogenetics+
Finding
Reduced- or no-function germline alleles translated into a metaboliser phenotype.
Specimen and assay
Blood/buccal specimen; a separate TPMT phenotype assay may be used under local protocols. Validated genotyping with adequate population coverage and correct haplotype assignment.
What the report needs
Each gene’s diplotype, allele function, metaboliser phenotype, limitations and a clinician-facing recommendation.
What a clinician may discuss
A clinician adjusts the starting strategy and monitoring intensity under the protocol; self-directed dose changes are unsafe.
Critical limitation
Genotype does not explain all myelotoxicity; laboratory monitoring remains essential regardless of result.
02 / REPORT PASSPORT
Six blocks without which ‘500-gene NGS’ guarantees very little.
Patient and specimen
Diagnosis, organ, stage, biopsy site/date, FFPE/cytology/plasma, tumour fraction and specimen age.
Assay and boundaries
Panel/version, DNA/RNA, covered exons/introns, SNV/indel/CNV/fusions/MSI/TMB/HRD, LoD and unassessed regions.
Run-specific quality
Mean/minimum depth, target coverage, QC, duplicates, contamination and reason for QNS or non-informative output.
Exact description
HGVS and genome build, VAF, copy number, fusion name and partners/breakpoints when resolved by the assay; MSI/TMB/HRD with units, threshold and algorithm version.
Clinical level
AMP/ASCO/CAP tier and/or ESCAT, tumour and stage, regulator/country, review date, resistance and relevant trials.
Safe conclusion
Main findings and negative limitations, possible germline origin, confirmation needs and molecular-tumour-board review.
03 / INHERITED RISK
Strong syndromes—not a generic ‘oncogene panel’.
Indications follow personal and family history, histology and sometimes tumour screening. A negative panel does not erase clinical risk.
Hereditary breast/ovarian and related cancer spectrum
Early onset, multiple primaries, ovarian cancer, male breast cancer, family clustering
Lynch syndrome
dMMR/MSI-H, colorectal or endometrial cancer, family spectrum
Adenomatous polyposis
Multiple adenomas; dominant and recessive inheritance differ
Li–Fraumeni syndrome
Very early and multiple tumours in a characteristic spectrum
Hereditary diffuse gastric cancer
Diffuse gastric histology and/or lobular breast cancer
Hamartomatous tumour syndromes
Polyps, mucocutaneous findings, macrocephaly or characteristic pigmentation
MEN2
Medullary thyroid cancer, phaeochromocytoma, family history
04 / TUMOUR BOARD
How a finding reaches a clinical decision.
- 1
Confirm biologyCorrect tumour, specimen, variant and functional class.
- 2
Assess evidenceSame indication, stage and line; ESCAT/AMP tier; current regulatory check.
- 3
Match the patientMorphology, prior treatment, organ function, interactions and preferences.
- 4
Document the decisionA team recommendation involving oncology and molecular pathology, alternatives, uncertainty, date and monitoring plan.
05 / CORE SOURCES
Regulatory status is rechecked on the decision date.
ESMO NGS recommendations 2024↗ESMO genomic reporting recommendations 2024↗AMP/ASCO/CAP somatic variant reporting↗ASCO somatic genomic testing PCO↗FDA FoundationOne CDx technical information↗FDA companion diagnostics↗FDA pharmacogenomic biomarkers↗EMA personalised oncology↗ГРЛС России↗
FDA and EMA are international regulatory reference points. Local guidelines, labels and authorisations must be rechecked before use. A biomarker in one jurisdiction does not automatically create an indication in another.