01Role and principlesWho benefits and the main preventive aims.
Inherited colorectal cancer assessment combines pathology, phenotype and pedigree rather than relying on a family-history slogan. Build a three-generation history with cancer site, polyp burden and age at diagnosis, verifying reports where possible and recognising that small families, adoption, early deaths and sex-specific organs can hide autosomal dominant disease. Red flags include colorectal or endometrial cancer at a young age, multiple Lynch-spectrum tumours, numerous adenomas, serrated polyposis and extracolonic features such as desmoid disease, duodenal adenomas, osteomas or congenital retinal pigment changes. Absence of a family history does not exclude a de novo APC variant, recessive MUTYH disease or an inherited variant in a small family.
Lynch syndrome reflects defective DNA mismatch repair. Colorectal tumours should undergo MMR immunohistochemistry for MLH1, MSH2, MSH6 and PMS2 or microsatellite-instability testing at diagnosis. Loss patterns direct sequential testing. MLH1 loss is often sporadic because of promoter hypermethylation, so NICE uses BRAF V600E followed, when negative, by MLH1 methylation before germline testing. Loss of MSH2, MSH6 or isolated PMS2 more directly raises a constitutional pathogenic variant. Tumour deficiency is a screening signal, not itself a germline diagnosis: biallelic somatic events and other explanations exist. Results affect immunotherapy and cancer treatment as well as relatives, so the pathology, oncology and genetics teams must close the loop.
FAP usually produces hundreds of adenomas during adolescence, although attenuated APC disease can present later with fewer proximal lesions. Endoscopic clearance postpones cancer but eventually becomes impractical or unsafe, so timing and type of colectomy depend on polyp burden, dysplasia, cancer, rectal involvement, desmoid risk, fertility, continence priorities and the ability to attend lifelong surveillance of retained rectum or ileal pouch. Upper-GI surveillance addresses duodenal and ampullary disease, and thyroid or desmoid assessment is phenotype-led. Biallelic MUTYH-associated polyposis can resemble attenuated FAP and has its own colon and upper-GI schedule. Multiple adenomas without an identified variant still deserve specialist phenotype-based management rather than reassurance from a negative panel.
Prevention is syndrome-specific. BSG recommends high-quality two-yearly colonoscopy for Lynch carriers, with gene-specific starting ages; prophylactic colectomy is not routine solely for being a carrier, but extent of cancer resection is a shared decision because metachronous risk competes with bowel function. NICE advises considering daily aspirin for more than two years in Lynch syndrome, but dose, bleeding risk, H pylori and timing need a shared specialist decision. FAP surveillance begins in early adolescence and transitions to surgery before cancer or unmanageable polyposis. Every pathway also includes communication: document the pathogenic variant using precise laboratory nomenclature, offer targeted predictive testing to adult relatives through genetics, arrange age-appropriate testing for childhood-onset FAP, and provide reproductive choices without coercion.
Key points
- Lynch syndrome is usually autosomal dominant and caused by a germline pathogenic variant affecting MLH1, MSH2, MSH6, PMS2 or EPCAM-mediated MSH2 silencing; it produces cancer predisposition without carpeting polyposis.
- Familial adenomatous polyposis is an autosomal dominant APC-associated syndrome with tens to thousands of adenomas and near-inevitable colorectal cancer without effective surveillance and prophylactic surgery.
- MUTYH-associated polyposis is autosomal recessive; biallelic carriers have important colorectal risk, while risk and management for a single variant differ and require contextual genetics advice.
- NICE recommends MMR immunohistochemistry or microsatellite-instability testing for every newly diagnosed colorectal cancer, followed by the appropriate tumour and germline sequence without delaying cancer treatment.
- Loss of MLH1 requires BRAF V600E and MLH1 promoter-hypermethylation assessment to distinguish many sporadic tumours before constitutional testing; other isolated MMR losses direct germline evaluation.
- BSG surveillance for Lynch syndrome is two-yearly colonoscopy from age 25 for MLH1 or MSH2 and from age 35 for MSH6 or PMS2, generally to age 75, unless individual factors alter it.
- For a confirmed APC-associated FAP carrier, colorectal surveillance normally starts at age 12 to 14 and repeats every one to three years according to phenotype while prophylactic surgery is planned.
- Cascade testing begins with the familial pathogenic variant, allowing relatives who carry it to enter surveillance and those who do not to avoid unnecessary syndrome-level procedures.
02Assessment and patient selectionRisk features, eligibility and important cautions.
Early colorectal or endometrial cancer, multiple metachronous Lynch-spectrum tumours and deficient MMR without a sporadic explanation support germline assessment, but some carriers have little family history.
Hundreds to thousands of colorectal adenomas developing from adolescence, often with an APC pathogenic variant and extracolonic features, require registry surveillance and planned prophylactic colorectal surgery.
Tens of adenomas, often proximal and later presenting, may reflect attenuated APC, biallelic MUTYH, POLE, POLD1 or another syndrome and merits specialist genomic assessment.
Affected siblings with unaffected parents or consanguinity supports autosomal recessive MAP, but pedigree appearance is unreliable. Management depends on biallelic versus monoallelic status and phenotype.
Loss of MLH1 and PMS2 with BRAF V600E or MLH1 promoter hypermethylation usually supports a sporadic tumour mechanism, though young age or an exceptional pedigree can require genetics review.
Anaemia, weight loss, bleeding, progressive bowel change or obstruction in a carrier is investigated as possible cancer immediately; scheduled surveillance must not become a reason to wait.
03Baseline assessmentMeasurements that guide the plan and track progress.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Three-generation verified pedigreeFirst step - Why
- Estimate inherited probability and identify the most informative affected relative and syndrome-specific cancers or polyps.
- Interpretation and limitations
- Record both sides of the family, ages, organs, pathology and current ages of unaffected relatives. Missing or small-family data reduces reassurance and may justify genetics assessment despite weak apparent history.
- 02
MMR immunohistochemistry or MSI testing - Why
- Screen every newly diagnosed colorectal cancer for deficient mismatch repair and guide sequential Lynch testing and treatment information.
- Interpretation and limitations
- Loss of a protein pair suggests the affected gene pathway; MSI-high indicates deficient repair but neither test alone proves inherited disease. Do not delay cancer treatment while completing the cascade.
- 03
BRAF V600E and MLH1 promoter methylation - Why
- Differentiate common sporadic MLH1-deficient colorectal cancers from tumours needing constitutional Lynch evaluation.
- Interpretation and limitations
- After abnormal MLH1 IHC, a BRAF variant or promoter hypermethylation supports sporadic silencing. When both are absent, NICE directs germline testing; exceptional clinical suspicion still warrants genetics review.
- 04
Targeted germline genomic testing - Why
- Confirm a heritable pathogenic variant after counselling using the NHS Genomic Test Directory eligibility and laboratory pathway.
- Interpretation and limitations
- A pathogenic or likely pathogenic variant can direct surveillance and cascade testing. A variant of uncertain significance must not be treated as a positive predictive result, and a negative panel may not erase a strong phenotype.
- 05
High-quality phenotype colonoscopy - Why
- Measure adenoma number, size, distribution and clearance feasibility and provide cancer prevention in Lynch and polyposis syndromes.
- Interpretation and limitations
- Count cumulative lesions across procedures. Rapid accrual or unmanageable burden changes surgery timing; quality, bowel preparation and complete excision are especially important where surveillance intervals are short.
- 06
Upper gastrointestinal endoscopy - Why
- Survey duodenum and ampulla in FAP or MAP from the syndrome-specific age and stage burden for intervention.
- Interpretation and limitations
- Use the current specialist staging system and visualise the ampulla appropriately. Upper-GI findings influence interval and expert resection but do not replace colorectal surveillance.
- 07
Gynaecological risk assessment - Why
- Provide Lynch carriers with symptom education and gene-, age- and family-completion-informed prevention discussion for endometrial and ovarian cancer.
- Interpretation and limitations
- Abnormal bleeding needs prompt diagnostic assessment. Surveillance tests have limitations; risk-reducing surgery and timing require specialist shared decision-making, not an automatic universal instruction.
04InterventionsLifestyle, treatment and escalation options.
01New colorectal cancerComplete universal tumour screeningFirst stepA person is newly diagnosed with colorectal cancer at any age.+
- 1Order or verify four-protein MMR immunohistochemistry or MSI testing and record responsibility for acting on the result without delaying staging or cancer treatment.
- 2For abnormal MLH1, follow the NICE BRAF V600E then MLH1 promoter-methylation sequence; for other abnormal loss patterns, progress to appropriately counselled germline testing.
- 3Discuss tumour findings in colorectal MDT because mismatch-repair status can affect prognosis and systemic-treatment choices as well as inherited-risk assessment.
- 4Refer a likely inherited or unexplained deficient-MMR result to genetics, communicate implications carefully and ensure relatives are not tested against an unconfirmed assumption.
02Confirmed LynchPrevent cancer by gene and contextA germline pathogenic variant confirms Lynch syndrome.+
- 1Enrol in high-quality two-yearly colonoscopy from the BSG gene-specific starting age, generally 25 for MLH1 or MSH2 and 35 for MSH6 or PMS2, individualised through the service.
- 2Discuss daily aspirin for more than two years using the NICE decision aid, considering gastrointestinal bleeding, ulcer history, allergy, interactions and uncertainty about optimal dose.
- 3Provide prompt assessment advice for bowel and abnormal uterine bleeding, and arrange gynaecological and other extracolonic prevention according to gene, sex, age and local specialist pathways.
- 4Offer targeted cascade testing and reproductive counselling through clinical genetics, giving each relative their own result and surveillance plan rather than sharing records informally.
03FAP or polyposisBalance clearance with prophylactic surgeryAPC-associated FAP or another clinically important adenomatous polyposis phenotype is confirmed.+
- 1Start FAP colorectal surveillance at age 12 to 14 and repeat every one to three years according to phenotype, with paediatric-to-adult transition and family support.
- 2Map rectal and colonic burden, dysplasia, cancer and adherence, then discuss colectomy timing and reconstruction before endoscopic control is lost or malignancy develops.
- 3Continue lifelong surveillance of retained rectum, ileal pouch and upper GI tract after surgery, because colectomy does not remove every syndrome-associated cancer risk.
- 4For biallelic MUTYH or unexplained multiple adenomas, apply the relevant BSG and genomic-service schedule rather than copying classical FAP ages and inheritance counselling.
04Family communicationTurn one diagnosis into preventionA clinically actionable germline pathogenic variant is identified in a family.+
- 1Confirm the exact gene and variant, inheritance pattern and index-person consent for supported family communication through the genetics service.
- 2Offer relatives targeted testing for the known familial variant, using age-appropriate consent and childhood testing only where childhood management changes, as in FAP.
- 3Place carriers into the correct colon, upper-GI or extracolonic pathway and release true non-carriers from variant-specific surveillance unless separate family risk remains.
- 4Revisit family structure over time for newly adult relatives, pregnancy planning and updated variant interpretation, maintaining confidentiality and avoiding coercive disclosure.
05Medicines and treatment safetyRegimens, contraindications and review points.
Aspirin chemoprevention in Lynch syndrome
NICE advises considering daily aspirin for more than two years; select the actual dose through shared specialist decision using current guidance and individual risk.Assess ulcer or bleeding history, anaemia, anticoagulants, allergy, asthma, kidney disease and H pylori context. Optimal dose is uncertain; do not extrapolate one trial dose as mandatory for everyone.
Bowel-cleansing preparation
Use a split-dose local regimen timed for high-quality surveillance, modified for age, renal or cardiac disease, constipation burden and the selected endoscopy list.Check obstruction, swallowing, dehydration, electrolytes and interacting medicines. Repeated poor preparation in a high-risk carrier needs pathway redesign rather than acceptance of a compromised examination.
06Targets, monitoring and follow-upResponse, safety and longer-term review.
- Maintain a hereditary-cancer register containing gene, exact variant, phenotype, operation, retained bowel and the next colon and upper-GI surveillance dates.
- Track every abnormal MMR or MSI result through BRAF, methylation, germline testing or documented sporadic resolution with a named responsible clinician.
- At each colonoscopy, record preparation, completion, cumulative polyp number, largest lesion, dysplasia and whether endoscopic clearance remains realistic.
- After FAP surgery, monitor the retained rectum or pouch, duodenum and desmoid-related symptoms according to phenotype; colectomy is not discharge from surveillance.
- During aspirin prevention, review bleeding, dyspepsia, anaemia, adherence and new anticoagulant exposure and revisit the dose-benefit decision periodically.
- Audit cascade-testing uptake without breaching confidentiality, offering recontact as relatives age or genomic interpretation changes.
07Special situationsVariants, exceptions and circumstances that change the usual approach.
Tumour deficient is not germline
MMR loss or MSI-high status identifies a repair phenotype. Sequential somatic and constitutional testing is required because sporadic MLH1 silencing and double-somatic events can mimic Lynch syndrome.
Family history can hide
A small family, few female relatives, adoption or early competing deaths can conceal dominant inheritance. Universal tumour testing protects patients whom pedigree criteria miss.
Inheritance changes siblings
FAP and Lynch are usually dominant, giving first-degree relatives a one-in-two prior risk when a parent carries the variant. Biallelic MUTYH disease is recessive, making sibling and partner testing questions different.
Negative is not always normal
A negative contemporary panel may leave unexplained multiple adenomas or a striking family cluster. Phenotype-based surveillance can remain appropriate while evidence and testing evolve.
Colectomy changes anatomy not DNA
FAP surgery prevents much colorectal cancer risk but retained rectum, pouch, duodenum and other tissues remain susceptible. Lifelong specialist follow-up is part of the operation.
Testing can release risk
Targeted cascade testing not only finds carriers; it can spare true non-carriers decades of syndrome-specific colonoscopy, anxiety and procedural harm.
08Common pitfallsFrequent interpretation and management errors.
- 01
Restricting Lynch tumour screening to young patients or those with an obvious family history.
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Calling MLH1 loss Lynch syndrome before BRAF and promoter-methylation assessment.
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Using a variant of uncertain significance as if it were a pathogenic family result.
- 04
Assuming a negative gene panel removes surveillance need in a compelling polyposis phenotype.
- 05
Delaying FAP surgery until cancer develops despite endoscopically unmanageable burden.
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Stopping all surveillance after colectomy and overlooking retained rectum, pouch or duodenum.
- 07
Prescribing aspirin prevention without discussing bleeding risk, uncertain optimal dose and continuing colonoscopy.