Clinical Genetics: Cancer genetics and inherited cardiovascular conditions

• Cancer genetics: Principles of Inherited Cancer | Family History of Breast and Ovarian Cancer | BRCA1 and BRCA2 | Other Breast Cancer Genes | Lynch Syndrome | Polyposis Syndromes | Family History of Colorectal Cancer | MEN1, MEN2, von Hippel–Lindau and Paraganglioma Syndromes | Li–Fraumeni and Other Cancer Syndromes
• Cardiovascular genetics: Familial Hypercholesterolaemia | Inherited Cardiomyopathies | Inherited Arrhythmia Syndromes | Sudden Cardiac Death in the Young - Family Screening | Inherited Aortopathy and Other Vascular Conditions
• Revision: Inherited Cancer and Cardiac Conditions at a Glance | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Cancer genetics and inherited cardiovascular conditions - page 5 of the Clinical Genetics chapter. These are the areas where genetics most often changes adult care: finding a BRCA or Lynch variant allows screening, risk-reducing surgery and targeted treatment; finding familial hypercholesterolaemia or an inherited arrhythmia allows statins, ICDs and cascade testing that prevent early deaths. Around 5–10% of cancers are due to a strongly inherited variant - the key skill is spotting the family that needs referral.
Your four questions for every family with cancer or sudden death: How many relatives, which cancers or cardiac events, and at what ages? Does the pattern fit a known syndrome? Does the patient or family meet criteria for genetic testing or enhanced surveillance? What prevention can we offer if a variant is found?

Principles of Inherited Cancer

• Most cancers are sporadic (somatic changes); about 5–10% are due to a high-risk inherited (germline) variant; others reflect moderate-risk genes and polygenic risk.
• Tumour suppressor genes (BRCA1, BRCA2, TP53, APC, RB1, mismatch repair genes) - the inherited variant is the "first hit"; cancer develops after a second hit in the other copy (Knudson's two-hit hypothesis - explains early onset and multiple tumours). Inheritance is autosomal dominant, though cellular behaviour is recessive.
• Oncogenes (RET in MEN2, MET) - a single activating variant is enough.
• DNA repair genes - mismatch repair (Lynch), homologous recombination (BRCA - PARP inhibitor sensitivity), base excision repair (MUTYH - recessive).
• Red flags for inherited cancer:
  • Young age at diagnosis (e.g. breast under 40, colorectal under 50).
  • Multiple relatives on the same side with the same or related cancers (breast–ovarian–prostate–pancreatic; colorectal–endometrial).
  • Multiple primary cancers or bilateral cancer in one person.
  • Rare cancers - male breast cancer, medullary thyroid cancer, adrenocortical carcinoma, phaeochromocytoma, retinoblastoma, sarcoma in childhood.
  • Distinctive pathology - triple-negative breast cancer, high-grade serous ovarian cancer, mismatch repair-deficient tumours, numerous colorectal polyps.
  • Ancestry - Ashkenazi Jewish (BRCA founder variants).

Family History of Breast and Ovarian Cancer

• NICE CG164 (familial breast cancer) - primary care takes a family history (first- and second-degree relatives) and refers to secondary care or a family history clinic if criteria are met, e.g.:
  • One first-degree relative with breast cancer under 40.
  • One first-degree male relative with breast cancer.
  • One first-degree relative with bilateral breast cancer (first under 50).
  • Two first-degree relatives, or one first-degree and one second-degree relative, with breast cancer.
  • A relative with ovarian cancer plus breast cancer in the family.
  • Three or more relatives with breast cancer, or Jewish ancestry with relevant history.
• Risk categories (NICE) - near population, moderate (lifetime risk 17–30%) and high (30% or more, or 8% or more in the next 10 years for those aged 40–49).
• Genetic testing - offered if the combined probability of BRCA1/BRCA2 (or relevant genes) is 10% or more (assessed with tools such as Manchester score or CanRisk/BOADICEA); NHS Test Directory criteria now also allow testing based on tumour features (e.g. triple-negative breast cancer under 60, high-grade non-mucinous epithelial ovarian cancer at any age).
• NHS Jewish BRCA Testing Programme - free BRCA testing for anyone in England with at least one Jewish grandparent (founder variants - about 1 in 40 Ashkenazi Jewish people carry one).
• Risk management for moderate or high risk without a known variant - enhanced mammographic surveillance from 40 (annual), MRI in selected high-risk women, chemoprevention - tamoxifen (premenopausal) or anastrozole (postmenopausal) for 5 years.
• Lifestyle - limit alcohol, maintain healthy weight, physical activity, breastfeeding; discuss HRT and contraception risks.

BRCA1 and BRCA2

• Autosomal dominant - homologous recombination DNA repair genes; about 1 in 400 in the general population (1 in 40 in Ashkenazi Jewish people).
• Approximate lifetime risks (to age 80):

  Cancer	BRCA1	BRCA2
  Female breast	About 70% (often triple-negative)	About 70% (often ER-positive)
  Ovarian (incl. fallopian tube, peritoneal)	About 40–45%	About 15–20%
  Male breast	Slightly raised	About 5–8%
  Prostate	Slightly raised	Raised - earlier, more aggressive
  Pancreas	Slightly raised	Raised (about 3–5%)

• Breast surveillance - annual MRI from about 25–30 (NHS Breast Screening Programme very high risk protocol) and annual mammography from 40 (check current NHSBSP ages).
• Risk-reducing surgery:
  • Bilateral risk-reducing mastectomy (with or without reconstruction) - reduces breast cancer risk by about 90% or more.
  • Risk-reducing bilateral salpingo-oophorectomy - at about 35–40 for BRCA1 and 40–45 for BRCA2, once childbearing is complete - reduces ovarian cancer risk by about 80–95% (ovarian screening isn't effective); HRT until the age of natural menopause if no breast cancer (bone and cardiovascular health).
• Treatment implications - PARP inhibitors (olaparib, niraparib) for BRCA-associated ovarian, breast, prostate and pancreatic cancer; platinum sensitivity; surgical choices (mastectomy vs breast conservation; contralateral surgery).
• Men with BRCA2 - breast awareness; consider PSA testing from about 40 (specialist advice).
• Reproductive options - prenatal diagnosis or PGT-M (HFEA-approved).
• Cascade testing - first-degree relatives (both sexes) have a 50% chance of carrying the variant.

Other Breast Cancer Genes

Lynch Syndrome

• The commonest inherited bowel cancer syndrome - about 1 in 300 people (mostly undiagnosed); autosomal dominant mismatch repair (MMR) gene variants - MLH1, MSH2, MSH6, PMS2 (and EPCAM deletions).
• Cancers - colorectal (often right-sided, under 50; lifetime risk up to about 50% for MLH1 and MSH2, lower for MSH6 and PMS2), endometrial (up to about 40–50% in women - often the "sentinel" cancer), ovarian, gastric, small bowel, urothelial (ureter and renal pelvis), pancreatic, biliary, brain, sebaceous skin tumours (Muir–Torre).
• Universal tumour testing:
  • All colorectal cancers (NICE DG27) and all endometrial cancers (NICE DG42) are tested for MMR deficiency - immunohistochemistry (loss of MMR proteins) or microsatellite instability (MSI).
  • If MLH1 is lost - test for BRAF V600E or MLH1 promoter hypermethylation (both suggest a sporadic cancer); if absent - germline testing.
• Clinical criteria (historical) - Amsterdam II ("3–2–1" - 3 relatives with Lynch-associated cancers, 2 successive generations, 1 under 50, FAP excluded) and revised Bethesda criteria.
• Management (BSG/ACPGBI/UKCGG 2019 and NICE):
  • Colonoscopy every 2 years - from 25 for MLH1 and MSH2, from 35 for MSH6 and PMS2, until 75.
  • Daily aspirin for at least 2 years to reduce colorectal cancer risk (NICE NG151 - discuss benefits and bleeding risk; CaPP3 trial informs dose).
  • Risk-reducing hysterectomy and bilateral salpingo-oophorectomy - offer at around 35–40 or once family complete (NICE NG151 / BGCS).
  • Gynaecological symptom awareness (abnormal bleeding - urgent assessment); H. pylori testing and treatment (gastric cancer risk).
• Treatment implications - MMR-deficient (MSI-high) cancers respond well to immune checkpoint inhibitors (e.g. pembrolizumab).
• Constitutional MMR deficiency - biallelic variants - childhood cancers and café-au-lait patches.

💡 Clinical Pearl: Endometrial cancer is often the first cancer in women with Lynch syndrome. A woman under 50 with endometrial cancer and a family history of bowel cancer - check the MMR result on her tumour and refer if deficient without MLH1 methylation.

Polyposis Syndromes

• Familial adenomatous polyposis (FAP) - autosomal dominant APC (chromosome 5q21); about 1 in 10,000; about a quarter de novo.
  • Hundreds to thousands of colorectal adenomas from the teens - colorectal cancer almost certain by 40 without surgery.
  • Extracolonic - duodenal and periampullary adenomas and cancer (upper GI endoscopy from about 25), desmoid tumours (especially after surgery - major cause of death after colectomy), osteomas, epidermoid cysts and dental anomalies (Gardner syndrome), CHRPE (congenital hypertrophy of retinal pigment epithelium), papillary thyroid cancer, hepatoblastoma in children, medulloblastoma (Turcot).
  • Management - predictive testing of children at around 12–14; colonoscopy from then (annual or as advised); prophylactic colectomy (usually late teens or early 20s - ileorectal anastomosis or restorative proctocolectomy with ileal pouch).
  • Attenuated FAP - fewer (under 100) polyps, later onset.
• MUTYH-associated polyposis - autosomal recessive - 10–100s of adenomas; often no family history in parents; siblings at 25% risk; colonoscopy surveillance or colectomy.
• Peutz–Jeghers syndrome (STK11, autosomal dominant) - pigmented macules on lips, buccal mucosa and fingers, hamartomatous polyps in the small bowel (intussusception in children), high lifetime cancer risk (GI, breast, pancreas, ovary, cervix, testis) - capsule endoscopy, colonoscopy, breast and pancreatic surveillance.
• Juvenile polyposis syndrome (SMAD4, BMPR1A) - juvenile (hamartomatous) polyps, GI bleeding, colorectal and gastric cancer; SMAD4 - overlap with HHT.
• Serrated polyposis syndrome - multiple serrated polyps; usually no germline cause identified.
• Cowden syndrome (PTEN) - mixed polyps, breast, thyroid, endometrial and kidney cancer, macrocephaly, skin lesions.

Family History of Colorectal Cancer

• Most people with one older relative with bowel cancer are at near-population risk - routine NHS Bowel Cancer Screening (FIT every 2 years from 50 in England, being lowered across the UK).
• Moderate risk (BSG/ACPGBI/UKCGG 2019) - e.g. one first-degree relative diagnosed under 50, or two first-degree relatives at any age - a one-off colonoscopy at 55 (follow local family history guidance).
• High-risk families without a known syndrome (e.g. Amsterdam-like but MMR-proficient - "familial colorectal cancer type X") - colonoscopy every 5 years from 40 to 75.
• Refer to clinical genetics - suspected Lynch or polyposis, MMR-deficient tumour without methylation, 10 or more adenomas (cumulative), early-onset cancer, multiple primaries.
• Test the affected relative's tumour first where possible - it guides who needs germline testing.

MEN1, MEN2, von Hippel–Lindau and Paraganglioma Syndromes

• Multiple endocrine neoplasia type 1 - autosomal dominant MEN1 (menin, chromosome 11) - "the 3 Ps":
  • Parathyroid hyperplasia (about 95% - primary hyperparathyroidism, often the first feature, under 30).
  • Pancreatic and duodenal neuroendocrine tumours - gastrinoma (Zollinger–Ellison - multiple peptic ulcers, diarrhoea), insulinoma, non-functioning.
  • Pituitary adenomas - prolactinoma commonest.
  • Also adrenal and thymic or bronchial carcinoids, lipomas, angiofibromas.
  • Biochemical and imaging surveillance from childhood.
• MEN2 - autosomal dominant RET proto-oncogene (gain of function):
  • MEN2A - medullary thyroid cancer (almost all - raised calcitonin), phaeochromocytoma (about 50%), primary hyperparathyroidism; cutaneous lichen amyloidosis; Hirschsprung disease.
  • MEN2B - medullary thyroid cancer (early and aggressive), phaeochromocytoma, mucosal neuromas (lips, tongue), marfanoid habitus, intestinal ganglioneuromatosis; no hyperparathyroidism.
  • Prophylactic total thyroidectomy guided by the RET variant - within the first year for MEN2B; by about 5 years for high-risk MEN2A variants; later with calcitonin monitoring for moderate-risk variants.
  • Always exclude phaeochromocytoma (plasma metanephrines) before thyroid or any surgery.
  • Test all patients with medullary thyroid cancer for germline RET.
• Von Hippel–Lindau syndrome - autosomal dominant VHL (chromosome 3p) - haemangioblastomas (cerebellum, spinal cord, retina), clear cell renal cell carcinoma (often multiple, bilateral), renal and pancreatic cysts, phaeochromocytoma, pancreatic NETs, endolymphatic sac tumours, epididymal cystadenomas; polycythaemia (erythropoietin). Lifelong surveillance (retinal exams, MRI brain/spine and abdomen, metanephrines); belzutifan (HIF-2α inhibitor) for VHL-related tumours (check UK availability).
• Hereditary phaeochromocytoma and paraganglioma - up to 40% of phaeochromocytomas and paragangliomas are inherited - SDHB (high malignancy risk), SDHD (head and neck paragangliomas - paternal transmission), SDHC, SDHA, VHL, RET, NF1, MAX, TMEM127 - offer germline testing to all.

Li–Fraumeni and Other Cancer Syndromes

• Li–Fraumeni syndrome - autosomal dominant TP53 - very high lifetime cancer risk (about 90% in women, 70% in men) - sarcomas (soft tissue, osteosarcoma), early-onset breast cancer, brain tumours, adrenocortical carcinoma, leukaemia; often in childhood.
  • Surveillance - annual whole-body MRI, brain MRI, breast MRI from 20, abdominal ultrasound in children (Toronto protocol).
  • Avoid ionising radiation where possible (radiotherapy-induced second cancers; CT minimised); mastectomy preferred over breast conservation with radiotherapy.
• Hereditary retinoblastoma - RB1 (chromosome 13) - leukocoria (white pupil reflex - urgent ophthalmology), squint; bilateral or multifocal tumours imply a germline variant (Knudson's two-hit model); later risk of osteosarcoma and soft tissue sarcoma.
• Hereditary diffuse gastric cancer - CDH1 - signet ring cell gastric cancer (endoscopic screening unreliable) - prophylactic total gastrectomy in early adulthood; lobular breast cancer (MRI surveillance).
• Gorlin syndrome (naevoid basal cell carcinoma syndrome - PTCH1) - multiple basal cell carcinomas from young adulthood, odontogenic keratocysts of the jaw, palmar and plantar pits, bifid ribs, calcified falx, macrocephaly, medulloblastoma in children - avoid radiotherapy (triggers BCCs) and sun exposure.
• BAP1 tumour predisposition - uveal melanoma, mesothelioma, cutaneous melanoma, renal cancer.
• Familial melanoma (CDKN2A) - melanoma and pancreatic cancer.
• Hereditary leiomyomatosis and renal cell cancer (FH gene) - cutaneous and uterine leiomyomas, aggressive papillary renal cancer.
• Birt–Hogg–Dubé (FLCN) - fibrofolliculomas, lung cysts with pneumothorax, renal tumours.
• Prostate cancer - consider germline testing (BRCA2, MMR genes, HOXB13) in metastatic or early-onset disease and strong family histories.

Familial Hypercholesterolaemia

• The commonest inherited cardiovascular condition - about 1 in 250 people (heterozygous); most are undiagnosed. Autosomal dominant - LDLR (most), APOB, PCSK9 (gain of function). Homozygous FH (about 1 in 300,000) - LDL often over 13 mmol/L, cardiovascular disease in childhood.
• Untreated - about 50% of men have coronary heart disease by 50, and 30% of women by 60.
• Clinical features - very high LDL cholesterol; tendon xanthomata (Achilles, extensor tendons of the hands); corneal arcus under 45; xanthelasma (non-specific); premature coronary heart disease; family history of early MI.
• Suspect FH (NICE CG71) - total cholesterol over 7.5 mmol/L in adults (or LDL over 4.9) and/or a personal or family history of premature coronary heart disease (under 60 in a first-degree relative); exclude secondary causes (hypothyroidism, nephrotic syndrome, cholestasis, drugs).
• Diagnosis - Simon Broome criteria or Dutch Lipid Clinic Network score (over 5 - offer DNA testing); genetic testing confirms and enables cascade testing.
• Treatment:
  • High-intensity statin (e.g. atorvastatin 20–80 mg) aiming for at least a 50% LDL reduction; add ezetimibe.
  • PCSK9 inhibitors (evolocumab, alirocumab) or inclisiran if LDL remains high (NICE criteria); bempedoic acid in some.
  • Children - consider statins by age 10 (specialist); lifestyle advice early.
  • Homozygous FH - lipoprotein apheresis, evinacumab, lomitapide (specialist).
  • Women - stop statins 3 months before planned conception.
• Risk scores like QRISK3 don't apply - people with FH are already high risk.
• Systematic cascade testing of first-, second- and third-degree relatives (NICE) - finding one patient identifies several more.
• Lipoprotein(a) - a genetically determined independent risk factor - measure once in adults with premature CVD or FH (check local and NICE advice).

Inherited Cardiomyopathies

• Hypertrophic cardiomyopathy (HCM) - about 1 in 500; autosomal dominant sarcomere genes (MYH7, MYBPC3 - most); variable penetrance.
  • Features - breathlessness, chest pain, palpitations, exertional syncope, sudden cardiac death (a leading cause in young people and athletes); ejection systolic murmur louder with Valsalva or standing (LVOT obstruction); ECG - LVH, deep T-wave inversion; echo or cardiac MRI - wall thickness 15 mm or more.
  • Management - beta-blockers or verapamil; mavacamten (cardiac myosin inhibitor) for symptomatic obstructive HCM; septal myectomy or alcohol septal ablation; ICD guided by the HCM Risk-SCD score; avoid dehydration, vasodilators and digoxin in obstruction; anticoagulate if AF.
  • Mimics - athlete's heart, hypertension, Fabry disease, amyloidosis, Danon disease, Friedreich's ataxia, Noonan syndrome.
• Dilated cardiomyopathy - about a third are familial - TTN (titin - commonest), LMNA (conduction disease, arrhythmias, sudden death - early ICD consideration), DSP, FLNC, RBM20; DMD carriers; screen relatives.
• Arrhythmogenic cardiomyopathy (ARVC) - desmosomal genes (PKP2, DSP, DSG2) - fibrofatty replacement of the RV; ventricular arrhythmias and sudden death in young people and athletes; ECG - T-wave inversion V1–V3, epsilon waves; cardiac MRI; avoid competitive and endurance exercise; beta-blockers; ICD.
• Hereditary transthyretin amyloidosis - TTR variants (e.g. V122I - common in people of West African ancestry) - heart failure with LVH, neuropathy, carpal tunnel syndrome - tafamidis, patisiran, vutrisiran (NICE criteria).
• Left ventricular non-compaction and restrictive cardiomyopathy - some genetic.
• Screening relatives - ECG and echo (or cardiac MRI), repeated over time (age-related penetrance); genetic testing if a familial variant is known.

Inherited Arrhythmia Syndromes

• Long QT syndrome - about 1 in 2,000; autosomal dominant (Romano–Ward); recessive Jervell and Lange-Nielsen (with deafness).
  • LQT1 (KCNQ1) - events during exercise, especially swimming.
  • LQT2 (KCNH2) - events with sudden noise (alarm clock), emotion and postpartum.
  • LQT3 (SCN5A) - events at rest or sleep.
  • Presentation - syncope, seizures (often misdiagnosed as epilepsy), torsades de pointes, sudden death; QTc over 480 ms (or 460 with symptoms) - Schwartz score.
  • Management - non-selective beta-blockers (nadolol, propranolol); avoid QT-prolonging drugs (CredibleMeds list) and hypokalaemia or hypomagnesaemia; ICD for high risk or recurrent events; left cardiac sympathetic denervation; LQT3 - mexiletine.
• Brugada syndrome - SCN5A in about 20% - coved ST elevation in V1–V2 (type 1 pattern - spontaneous or after ajmaline challenge); ventricular fibrillation at rest or during sleep; more common in men and people of South-East Asian ancestry; fever unmasks it - treat fever promptly with paracetamol; avoid triggering drugs (brugadadrugs.org - e.g. some antiarrhythmics, tricyclics, lithium, propofol infusions, cocaine) and excess alcohol; ICD if survived arrest or arrhythmic syncope.
• Catecholaminergic polymorphic VT (CPVT) - RYR2 (dominant) or CASQ2 (recessive) - exercise- or emotion-induced syncope and bidirectional VT in children; normal resting ECG - exercise test; beta-blockers, flecainide, ICD.
• Short QT syndrome - QTc under about 340 ms - AF and VF.
• Wolff–Parkinson–White - usually sporadic; PRKAG2 familial form with LVH.
• Progressive cardiac conduction disease - SCN5A, LMNA.

⚠️ Safety Pearl: "Epilepsy" that comes on during exercise, swimming, a sudden loud noise or sleep may be an inherited arrhythmia. Do an ECG and check the QTc in anyone with unexplained seizures or syncope, and ask about sudden deaths in the family.

Sudden Cardiac Death in the Young - Family Screening

• Sudden cardiac death under 35–40 - causes include cardiomyopathies (HCM, ARVC, DCM), channelopathies (long QT, Brugada, CPVT), coronary anomalies, premature coronary disease (FH), myocarditis, aortic dissection (Marfan).
• Sudden arrhythmic death syndrome (SADS) - a structurally normal heart at expert post-mortem - suggests a channelopathy.
• After a sudden death:
  • Expert cardiac pathology post-mortem (coroner).
  • Retain tissue or blood for DNA - "molecular autopsy" (genetic testing of the deceased).
  • Refer first-degree relatives to an inherited cardiac conditions clinic.
• Family evaluation - history (syncope, palpitations, seizures), ECG (resting and with high leads), echocardiogram, exercise test, ambulatory monitoring, cardiac MRI, ajmaline provocation (Brugada); genetic testing if a variant is found in the deceased or an affected relative; repeat screening for children and young adults over time.
• Yield - an inherited condition is found in a significant proportion of SADS families.
• Support - bereavement support (e.g. Cardiac Risk in the Young - CRY), clear communication, psychological support.
• Survivors of cardiac arrest - full investigation for inherited causes; ICD.

Inherited Aortopathy and Other Vascular Conditions

• Heritable thoracic aortic disease - Marfan (FBN1), Loeys–Dietz (TGFBR1/2, SMAD3, TGFB2), vascular Ehlers–Danlos (COL3A1), familial thoracic aortic aneurysm (ACTA2, MYH11), bicuspid aortic valve (familial in some - screen first-degree relatives with echo), Turner syndrome.
• Thoracic aortic dissection under 60 or without hypertension - consider genetic testing and screen relatives (echo or MRI).
• Familial intracranial aneurysm - two or more first-degree relatives with aneurysms or SAH - MR angiography screening; ADPKD.
• Hereditary haemorrhagic telangiectasia - see page 4.
• Inherited thrombophilia - factor V Leiden (about 5% of white Europeans - heterozygotes have a modest VTE risk increase), prothrombin G20210A, deficiencies of antithrombin, protein C and protein S (rarer, higher risk); testing rarely changes management - NICE NG158 advises not testing routinely after a first unprovoked VTE; consider in specific situations (e.g. first-degree relatives of people with antithrombin deficiency before pregnancy or combined hormonal contraception).
• CADASIL (NOTCH3 - autosomal dominant) - migraine with aura, recurrent subcortical strokes, mood disturbance and vascular dementia in mid-adulthood; white matter changes in anterior temporal poles and external capsule on MRI.

Inherited Cancer and Cardiac Conditions at a Glance

Spot the Diagnosis

Exam-style Scenarios

1. A 38-year-old woman's mother had ovarian cancer at 52 and her maternal aunt breast cancer at 40. She is well and asks about her risk.
Answer: High-risk family history - refer to clinical genetics.

• Ideally test an affected living relative first (to find the family variant); if not possible, assess her probability (Manchester score or CanRisk) for direct testing.
• If BRCA positive - annual breast MRI, risk-reducing mastectomy option, risk-reducing salpingo-oophorectomy at 35–45 once family complete.
• If no variant identified - manage on family history risk (enhanced screening, consider chemoprevention).

2. A 44-year-old man has right-sided colon cancer. Immunohistochemistry shows loss of MSH2 and MSH6. His father had bladder (urothelial) cancer.
Answer: Probable Lynch syndrome (MSH2).

• Germline MMR testing; clinical genetics referral; cascade testing of relatives.
• If confirmed - 2-yearly colonoscopy; daily aspirin; female relatives with the variant offered risk-reducing gynaecological surgery.
• MMR-deficient tumour - likely to respond to immunotherapy if advanced.

3. A 16-year-old girl collapses while swimming. She recovers. Her ECG shows a QTc of 500 ms. Her uncle drowned at 20.
Answer: Long QT syndrome (probably LQT1).

• Cardiology and inherited cardiac conditions referral; beta-blocker (nadolol); avoid QT-prolonging drugs; keep potassium and magnesium normal.
• Genetic testing (KCNQ1, KCNH2, SCN5A); ICD if high risk.
• ECG and genetic testing for first-degree relatives; no unsupervised swimming.

4. A 35-year-old man has total cholesterol 9.2 mmol/L and LDL 7.1 mmol/L. He has thickened Achilles tendons. His father had an MI at 45.
Answer: Familial hypercholesterolaemia (definite by Simon Broome - tendon xanthomata).