Identify inherited ovarian and endometrial cancer risk, distinguish tumour from constitutional findings, apply current NHS testing pathways, and coordinate cascade testing and gene-specific prevention.
Hereditary ovarian cancer describes an inherited predisposition rather than one histological diagnosis. A constitutional pathogenic variant is present throughout the body and may be passed to relatives. A somatic variant arises within the tumour and can alter treatment while carrying no automatic implication for relatives. Tumour testing may reveal a possible constitutional variant, but a non-tumour sample is needed when germline confirmation is indicated.
BRCA1 and BRCA2 account for a large proportion of hereditary epithelial tubo-ovarian cancer. RAD51C, RAD51D, BRIP1 and PALB2 also influence homologous-recombination repair and confer gene-specific ovarian risk. Lynch syndrome results from constitutional mismatch-repair pathway failure, most often involving MLH1, MSH2, MSH6 or PMS2; deletions affecting EPCAM can silence neighbouring MSH2.
Cancer risk is not interchangeable between genes. BRCA1 and BRCA2 strongly associate with high-grade serous tubo-ovarian cancer, whereas Lynch-associated ovarian tumours are more often endometrioid or clear-cell. MSH6 and PMS2 generally differ from MLH1 and MSH2 in penetrance and age pattern. The exact variant, age, organs present, family history, previous cancers and competing health risks must therefore shape advice.
Constitutional BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 or PALB2 variants can impair high-fidelity DNA repair and increase gene-specific tubo-ovarian cancer risk.
Pathogenic MLH1, MSH2, MSH6 or PMS2 variants, and some EPCAM deletions, produce Lynch syndrome with variable endometrial, colorectal, ovarian and other cancer risks.
Historical population bottlenecks make particular pathogenic variants more frequent in some Jewish and Greenlander ancestries, enabling defined population-based testing pathways.
Inheritance may be obscured by small families, transmission through men, early deaths, adoption, incomplete diagnoses or relatives who underwent preventive surgery.
A constitutional variant supplies one impaired allele, while loss or inactivation of the remaining functional allele within a cell promotes malignant transformation.
Defective repair of double-strand DNA breaks creates genomic instability, characteristic tumour evolution and potential sensitivity to platinum and targeted treatment.
Failure to correct replication errors causes microsatellite instability and accumulation of mutations, producing Lynch-associated tumour phenotypes and immunogenicity.
The same inherited variant does not affect every organ equally because hormonal exposure, tissue biology, modifier genes, age and environment shape cancer expression.
Invasive epithelial ovarian cancer or a recognised rare ovarian tumour should trigger counselling and genomic testing without waiting for a striking family history.
Every endometrial cancer should enter the Lynch tumour-testing pathway, with the pattern of mismatch-repair protein loss determining methylation and germline steps.
One first-degree relative or a maternal or paternal second-degree relative with ovarian cancer meets the NG241 genetics-referral criterion; broader early or multiple syndrome-associated cancers further shape panel selection.
A relative carrying a documented pathogenic variant permits targeted cascade testing, which is more informative than repeating a broad panel without identifying the family result.
At least one Ashkenazi Jewish, Sephardi Jewish or Greenlander grandparent qualifies for the NG241 founder-variant pathway even when no cancer history is known.
Most ovarian cancers are not explained by an inherited pathogenic variant, although tumour genomics may still reveal actionable somatic abnormalities.
A BRCA or mismatch-repair change confined to cancer tissue may influence treatment but does not establish inherited risk for blood relatives.
Insufficient evidence prevents classification as benign or pathogenic, so family management remains based on established variants and clinical risk.
A family can have meaningful history-based risk despite uninformative testing because current panels and knowledge do not explain every inherited pattern.
DICER1, SMARCA4, Peutz-Jeghers and other rare syndromes associate with particular ovarian histologies and require phenotype-directed specialist testing.
Carriers can develop ovarian, fallopian-tube or primary peritoneal malignancy, and residual peritoneal risk remains after salpingo-oophorectomy.
Lynch syndrome creates substantial risks beyond the ovary, making coordinated uterine and bowel prevention central to care.
A carrier may develop metachronous tumours in different organs, requiring lifelong coordination across genetics, oncology and surveillance services.
Results affect fertility timing, reproductive choices and blood relatives who may face their own testing and prevention decisions.
Preventive oophorectomy before natural menopause can cause vasomotor, sexual, skeletal, cardiovascular and psychological effects requiring anticipatory specialist care.
Tumour testing can select therapy, while constitutional testing determines inherited predisposition; one result may suggest the other but cannot automatically replace it.
BRCA and Lynch variants can pass through any biological parent, so an apparently sparse paternal history must not be discarded.
MLH1 and PMS2 are protein partners, as are MSH2 and MSH6; the immunohistochemical pattern helps select methylation and germline steps.
A variant of uncertain significance may later be reclassified, but it must not drive predictive testing or irreversible surgery while uncertainty remains.
Four-monthly algorithmic CA125 is a specialist option for defined carriers delaying surgery, not general screening and not proof that prevention is unnecessary.
Restricting Lynch testing after endometrial cancer to younger people or those with a convincing family history.
Calling a tumour BRCA or mismatch-repair result inherited without constitutional confirmation when required.
Using a variant of uncertain significance to recommend cascade testing or risk-reducing surgery.
Ignoring the paternal lineage, small family size, adoption or early deaths when interpreting an apparently negative pedigree.
Offering annual CA125 or ultrasound as a reassuring alternative to specialist gene-specific prevention.
Failing to investigate current bleeding or ovarian-cancer symptoms because a surveillance result was recently normal.
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An endometrial cancer shows loss of both MLH1 and PMS2 expression on mismatch-repair immunohistochemistry. What is the recommended next laboratory step?
National guidance is shown before implementation-dependent detail. Apply principles in context and verify current guidance when a decision affects care. Source check completed 27 Aug 2026; clinical approval remains outstanding.
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Take a three-generation history covering ovarian, fallopian-tube, primary peritoneal, breast, endometrial, colorectal, pancreatic, prostate, upper urinary tract, gastric, small-bowel, brain and relevant skin cancers. Record the relative, biological side of the family, tumour site, histology and age at diagnosis. Under NG241, a first-degree relative with ovarian cancer or a maternal or paternal second-degree relative with ovarian cancer is enough for genetics referral even when the intervening relative is unaffected. Verify diagnoses where possible because family descriptions such as stomach cancer or female cancer can conceal a different primary.
Do not use a reassuring-looking pedigree to exclude inherited risk. Small families, few female relatives, adoption, early deaths, prophylactic surgery, inaccurate diagnoses and inheritance through men can obscure the pattern. Conversely, several common late-onset cancers do not prove a syndrome. Validated probability tools and genetics review convert the history into a defensible testing decision.
NICE NG241 recommends genetic counselling and testing for people with invasive epithelial ovarian cancer and specified rare ovarian tumours. Mainstream testing can begin within oncology when trained staff obtain informed consent and support, with genetics referral for complex interpretation. Germline and tumour assays answer different questions, and tumour BRCA or homologous-recombination findings can affect systemic treatment.
NICE HTG557 recommends offering Lynch-syndrome testing to everyone diagnosed with endometrial cancer. Tumour immunohistochemistry examines MLH1, PMS2, MSH2 and MSH6 expression. Loss of MLH1 alone or MLH1 with PMS2 requires MLH1 promoter hypermethylation testing because sporadic epigenetic silencing is common. If hypermethylation is absent, germline testing is offered. Loss of MSH2, MSH6 or isolated PMS2 leads to germline testing.
A pathogenic or likely pathogenic germline variant supports syndrome-specific management and targeted testing of blood relatives. A negative result may be informative when the known familial variant was tested, but an uninformative negative panel in a family without an identified variant does not erase history-based risk. A variant of uncertain significance is not evidence for predictive testing or irreversible preventive surgery.
NICE advises cascade testing for an unaffected first-degree relative of someone with a known pathogenic variant. A second-degree or more distant relative can be offered testing when an intervening blood relative cannot be tested or testing is clinically inappropriate. Explain possible outcomes, confidentiality boundaries, reproductive implications and the voluntary nature of sharing information.
Founder variants are more prevalent in some populations. NG241 recommends offering referral for counselling and founder-variant testing to people with at least one Ashkenazi Jewish, Sephardi Jewish or Greenlander grandparent even without a cancer history. Ancestry is one access route, not a biological shortcut, and people outside those groups still qualify through personal cancer, family history or a known familial variant.
After a pathogenic result, the familial ovarian cancer multidisciplinary team estimates absolute risk using the gene, age and verified family history, with a tool such as CanRisk when appropriate. The team also coordinates breast, bowel and other organ-specific pathways. Risk communication should use absolute numbers and time frames, acknowledge uncertainty and separate carrier probability from future cancer probability.
Risk-reducing bilateral salpingo-oophorectomy substantially lowers tubo-ovarian cancer risk but does not eliminate primary peritoneal cancer. NICE links the offer to completed family or no planned natural conception and total lifetime ovarian risk of at least 5%. Indicative lower age limits are 35 for BRCA1, 40 for BRCA2 and 45 for RAD51C, RAD51D, BRIP1 or PALB2 when the risk threshold is met. MLH1, MSH2 and MSH6 carriers may be offered hysterectomy with bilateral salpingo-oophorectomy no earlier than 35 because endometrial risk is also relevant.
Surveillance is not prevention. When a person with a qualifying variant delays or declines recommended surgery, NICE permits specialist serial four-monthly CA125 interpreted longitudinally by a validated algorithm, with at least annual review of surgery. It applies only to specified gene-and-age groups under the familial ovarian cancer team and cannot promise survival benefit or replace symptom assessment.
A person undergoing premenopausal oophorectomy needs fertility and menopause counselling before surgery. NICE recommends offering hormone replacement therapy until the average menopause age, usually around 51, when there is no previous breast cancer, with regimen type determined by whether a uterus remains. Previous breast cancer requires liaison with the breast cancer team.
Genetic risk never converts new symptoms into a surveillance issue. Postmenopausal bleeding requires endometrial assessment, while persistent ovarian-cancer symptoms, ascites or a mass follow the diagnostic pathway. A normal interval CA125 result cannot exclude a symptomatic cancer.