*Source: https://www.years.co/en/genetische-risikofaktoren* Genetic risk factors # Not every variant is a risk. What matters is what follows from it. A genetic finding is only worth something once a consequence follows from it. Which genes deliver that, which merely add context, and which are overrated in the marketing of genetic tests. Free intro call Book an appointment - 170+ curated risk genes - Classification by ACMG - Pharmacogenetics included - Physician-led discussion of findings In brief ## Which genetic risks actually count A genetic risk factor matters when it triggers a consequence. By that criterion three groups remain. Monogenic variants with high penetrance, such as BRCA1, BRCA2, the Lynch genes, LDLR and HFE, are covered by guidelines and change screening intervals or treatment. Pharmacogenetic findings such as CYP2C19, DPYD and TPMT demonstrably change the dosing of certain drugs and hold for life. Carrier status for recessive conditions matters for family planning. Polygenic risk scores and lifestyle genetics such as MTHFR or COMT provide context but justify no diagnosis and no treatment. A genetic finding also describes predisposition, not your current state. Fundamentals and methods: Genetic analysis explained What follows ## Three kinds of finding — and what each means for you. This distinction is the most important one in the field. It decides whether an action follows from a finding, or only a feeling. ### This changes your screening A variant in a single gene with a large effect. Lifetime risk is markedly raised, and specialist societies have defined screening schedules for it. What follows May justify a shorter screening interval, further diagnostics or treatment. ### This changes your medication Variants in drug-metabolising enzymes. They say nothing about disease risk, but a great deal about the effect and tolerability of medications. What follows Changes drug choice or dosing. Holds for life, needs establishing once. ### This changes nothing for now Hundreds to thousands of variants each with a tiny effect, combined into a score. Plus common variants such as MTHFR or COMT with small effect sizes. What follows Provides context. Triggers no diagnosis and no treatment; predictive performance outside European cohorts poorly documented. Concretely ## The genes where a finding changes something. An extract from the more than 170 clinically curated risk genes in the Ultimate analysis. The right-hand column names the evidence tier the type of finding sits on. Gene | Relates to | What follows from a pathogenic finding | Tier | BRCA1 / BRCA2 | Breast, ovarian, prostate and pancreatic cancer | Intensified early detection programme as specified by the relevant specialist society, counselling on risk-reducing options, testing offered to first-degree relatives | Guideline | MLH1, MSH2, MSH6, PMS2 (Lynch) | Colorectal cancer, endometrial cancer | Colonoscopy at markedly shorter intervals and from a markedly younger age than in standard screening, gynaecological surveillance | Guideline | LDLR, APOB, PCSK9 | Familial hypercholesterolaemia | Early and consistent lipid lowering, cascade screening in the family — the condition is common and commonly missed | Guideline | HFE | Hereditary haemochromatosis (iron overload) | Monitoring of ferritin and transferrin saturation, and on confirmation, phlebotomy — fully treatable when detected early | Guideline | CYP2C19 | Clopidogrel, proton pump inhibitors, some SSRIs | Change of drug or dose adjustment. A poor metaboliser gains little platelet inhibition from standard clopidogrel | Guideline | DPYD | Fluoropyrimidines in chemotherapy | Dose reduction or alternative regimen. Testing recommended before treatment starts, because the risk of severe toxicity rises substantially | Guideline | TPMT / NUDT15 | Thiopurines in autoimmune conditions | Dose adjustment to avoid myelosuppression | Guideline | CYP2D6 | Antidepressants, tamoxifen, codeine | Drug choice and dosing. With codeine additionally relevant to safety | Guideline | TTR | Hereditary transthyretin amyloidosis | Cardiological and neurological surveillance, specific therapies available | Guideline | LPA locus | Lipoprotein(a) and cardiovascular risk | Lp(a) is largely genetically determined. The value itself is measured directly in blood — the genetic finding explains it but does not replace it | Study-based | APOE | Alzheimer’s risk, lipid metabolism | No specific therapy. May shift the priority of cardiovascular and lifestyle prevention. Belongs in the conversation before the test | Study-based | Polygenic scores | Coronary heart disease, type 2 diabetes, individual cancers | Shifts a probability, justifies no diagnosis. May inform how other diagnostics are prioritised | Research-adjacent | MTHFR, COMT and similar | Homocysteine, neurotransmitter metabolism | No recommendation. Where a laboratory value answers the question directly, the detour via genetics is the worse route | Research-adjacent | BRCA1 / BRCA2 Guideline Relates to Breast, ovarian, prostate and pancreatic cancer What follows from a pathogenic finding Intensified early detection programme as specified by the relevant specialist society, counselling on risk-reducing options, testing offered to first-degree relatives MLH1, MSH2, MSH6, PMS2 (Lynch) Guideline Relates to Colorectal cancer, endometrial cancer What follows from a pathogenic finding Colonoscopy at markedly shorter intervals and from a markedly younger age than in standard screening, gynaecological surveillance LDLR, APOB, PCSK9 Guideline Relates to Familial hypercholesterolaemia What follows from a pathogenic finding Early and consistent lipid lowering, cascade screening in the family — the condition is common and commonly missed HFE Guideline Relates to Hereditary haemochromatosis (iron overload) What follows from a pathogenic finding Monitoring of ferritin and transferrin saturation, and on confirmation, phlebotomy — fully treatable when detected early CYP2C19 Guideline Relates to Clopidogrel, proton pump inhibitors, some SSRIs What follows from a pathogenic finding Change of drug or dose adjustment. A poor metaboliser gains little platelet inhibition from standard clopidogrel DPYD Guideline Relates to Fluoropyrimidines in chemotherapy What follows from a pathogenic finding Dose reduction or alternative regimen. Testing recommended before treatment starts, because the risk of severe toxicity rises substantially TPMT / NUDT15 Guideline Relates to Thiopurines in autoimmune conditions What follows from a pathogenic finding Dose adjustment to avoid myelosuppression CYP2D6 Guideline Relates to Antidepressants, tamoxifen, codeine What follows from a pathogenic finding Drug choice and dosing. With codeine additionally relevant to safety TTR Guideline Relates to Hereditary transthyretin amyloidosis What follows from a pathogenic finding Cardiological and neurological surveillance, specific therapies available LPA locus Study-based Relates to Lipoprotein(a) and cardiovascular risk What follows from a pathogenic finding Lp(a) is largely genetically determined. The value itself is measured directly in blood — the genetic finding explains it but does not replace it APOE Study-based Relates to Alzheimer’s risk, lipid metabolism What follows from a pathogenic finding No specific therapy. May shift the priority of cardiovascular and lifestyle prevention. Belongs in the conversation before the test Polygenic scores Research-adjacent Relates to Coronary heart disease, type 2 diabetes, individual cancers What follows from a pathogenic finding Shifts a probability, justifies no diagnosis. May inform how other diagnostics are prioritised MTHFR, COMT and similar Research-adjacent Relates to Homocysteine, neurotransmitter metabolism What follows from a pathogenic finding No recommendation. Where a laboratory value answers the question directly, the detour via genetics is the worse route Variants of uncertain significance occur in every comprehensive analysis. They are named as such and not reinterpreted into a recommendation. This table is an extract and not a complete list of the genes interpreted. How we classify every procedure: Evidence and scientific standards Context ## Why we do not sell polygenic scores as a result. Polygenic risk scores are a serious research instrument, and that is precisely why we treat them as one. - — A score shifts a probability. It does not say whether you will develop a condition, and it justifies no diagnosis. - — Calibration comes from the cohorts in which the score was developed. Outside European populations predictive performance is far less well documented. - — For most common conditions the score explains part of the variance, while blood pressure, ApoB, HbA1c, smoking and exercise explain the larger part. - — A high score rarely changes the recommendation. What it can change is the priority given to diagnostics that make sense anyway. In the report, polygenic scores therefore sit in their own section labelled as research-adjacent — separated from the findings that an action follows from. Afterwards ## What happens if something is found. A hereditary finding does not concern only you, and it is never delivered by PDF. - A personal medical consultation on the findings, with the evidence tier and the concrete consequence made explicit. - An adjusted screening schedule following the guidelines of the relevant specialist society, not house opinion. - Coordination of onward care: referral to human genetics centres or specialist clinics where specialised management is needed. - The question of family: a hereditary finding concerns siblings and children. Their testing requires counselling of its own, and the right not to know applies there too. Related: Family history · Genetics in a health check ## Frequently asked questions about genetic risk factors Which genetic risk factors actually matter? + A finding matters when it triggers a consequence. By that criterion three groups remain. First, monogenic variants with high penetrance, meaning ones that actually cause the condition in most carriers: BRCA1 and BRCA2 in breast and ovarian cancer, the Lynch genes in bowel cancer, LDLR, APOB and PCSK9 in familial hypercholesterolaemia, HFE in haemochromatosis. These findings are covered by guidelines and change screening intervals or treatment. Second, pharmacogenetics: CYP2C19, DPYD, TPMT and CYP2D6 demonstrably change the dosing of certain drugs. Third, carrier status for recessive conditions, relevant for family planning. Everything else provides context without justifying an action. What is the difference between monogenic and polygenic risk? + A monogenic risk traces back to a variant in a single gene and often has a large effect. A pathogenic BRCA1 variant markedly raises lifetime breast cancer risk, which is why concrete screening recommendations follow from it. A polygenic risk arises from hundreds or thousands of variants each with a tiny effect, combined into a score. The difference is not one of degree but of kind: a monogenic finding can justify a diagnosis, a polygenic score shifts a probability. Polygenic scores are also calibrated to the cohorts in which they were developed, which is why their predictive performance outside European populations is far less well documented. Should I know my ApoE status? + This is one of the few genetic questions where the honest answer is: it depends what you intend to do with it. ApoE4 raises the risk of Alzheimer’s disease, particularly in homozygous carriers. At the same time there is no approved therapy initiated on the basis of ApoE status, and many carriers never develop the disease. What the finding can change: the priority you give to cardiovascular health, sleep, hearing loss and exercise, meaning precisely the factors that count without genetics too. What it does not deliver: a prognosis. Which is why ApoE belongs in a conversation before the test, not in a report afterwards. What does pharmacogenetics deliver in practice? + It is the part of genetics with the clearest immediate benefit, because it changes an action rather than a probability. Four examples. CYP2C19 determines whether clopidogrel works for you; a poor metaboliser gains little protection from the standard drug. DPYD variants substantially raise the risk of severe side effects on fluoropyrimidines in chemotherapy, which is why testing is recommended before treatment starts. TPMT concerns thiopurines in autoimmune conditions. CYP2D6 affects numerous antidepressants and tamoxifen. The finding holds for life, making it one of the few genetic values you only need to establish once. How robust are MTHFR, COMT and similar lifestyle genes? + Considerably less robust than the marketing suggests. These variants are common, their effect sizes are small, and the leap from a gene variant to a supplement recommendation is not supported by the studies. The MTHFR C677T variant, for instance, has a measurable influence on homocysteine levels in some carriers, but the clinical consequence is disputed and a raised homocysteine value can be measured directly anyway. That is precisely the point: where a laboratory value answers the question directly, the detour via genetics is the worse route. We therefore classify these findings as research-adjacent and derive no recommendations from them. What happens if a relevant finding appears? + The finding is discussed in a personal medical consultation, never by portal or PDF alone. Where a pathogenic variant in a high-risk gene is found, three things follow. First, an adjusted screening schedule oriented to the guidelines of the relevant specialist society, such as shorter MRI intervals for BRCA carriers. Second, coordination of onward care: we refer to human genetics centres or specialist clinics where specialised management is needed. Third, the question of family, because a hereditary finding concerns siblings and children and their testing requires counselling of its own. A right not to know remains in place throughout. ## Also of interest Genetic analysis Panel, array, exome and genome explained Genetic health check How genetics is embedded in a complete check-up Family history When cancer, heart attack or dementia runs in the family Blood values in a check-up The values that say more about your next ten years ## A finding without a consequence is only information. In a free intro call we clarify which clinical question your family history raises, and which finding would genuinely change anything about it. Free intro call Book an appointment Medical Disclaimer This information is provided for general education and is not a substitute for professional medical advice, diagnosis or treatment. Please discuss findings and individual medical decisions with a qualified physician. Content is reviewed periodically against the current state of scientific evidence.