Synopsis
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 cancer assessment involves two related genomes: constitutional variants can be inherited and affect relatives, while tumour-only variants may guide treatment without being present in the rest of the body.
- Important ovarian-predisposition genes include BRCA1, BRCA2, RAD51C, RAD51D, BRIP1 and PALB2; Lynch syndrome involves mismatch-repair genes including MLH1, MSH2, MSH6 and PMS2, with some EPCAM deletions affecting MSH2.
- Inheritance is usually autosomal dominant, so each child of a heterozygous carrier has a one-in-two chance of inheriting the familial variant, but cancer risk and age of onset remain gene and family specific.
- Refer anyone with a first-degree relative with ovarian cancer or a maternal or paternal second-degree relative with ovarian cancer for genetic counselling and testing; an unaffected intervening relative does not remove eligibility.
- NICE recommends Lynch testing for everyone diagnosed with endometrial cancer, beginning with tumour mismatch-repair immunohistochemistry rather than germline testing every tumour indiscriminately.
- Loss of MLH1 or MLH1 and PMS2 leads to tumour MLH1 promoter hypermethylation testing; absent hypermethylation leads to germline testing, while loss of MSH2, MSH6 or isolated PMS2 leads directly to germline testing.
- A pathogenic or likely pathogenic result can guide risk management and targeted cascade testing; a variant of uncertain significance must not be treated as a disease-causing familial variant.
- Use the NHS National Genomic Test Directory and the personal cancer and family phenotype to select the correct panel rather than ordering one universal hereditary-cancer panel.
- Risk-reducing surgery is considered only after specialist assessment, completion of the family or a decision not to conceive naturally, and a total lifetime ovarian-cancer risk of at least 5%.
- CA125 surveillance does not prevent ovarian cancer and is not an equivalent substitute for indicated surgery; NICE restricts it to defined gene-and-age groups through a familial ovarian cancer multidisciplinary team when surgery is delayed or declined.
- NICE offers founder-variant testing pathways for people with at least one Ashkenazi Jewish, Sephardi Jewish or Greenlander grandparent even without a personal or family cancer history.
Key red flags
Every new diagnosis of endometrial cancer should trigger the recommended tumour testing pathway for Lynch syndrome rather than testing only people below an age threshold.
Invasive epithelial ovarian cancer and specified rare ovarian tumours should prompt genetic counselling and testing because results can affect treatment and relatives.
A first-degree relative with ovarian cancer, or a maternal or paternal second-degree relative with ovarian cancer even through an unaffected intervening relative, meets the NG241 referral criterion for genetic counselling and testing.
A known familial pathogenic variant without documented cascade testing or specialist risk management represents an actionable gap in care.
Early-onset, bilateral or multiple primary cancers, or clustering of ovarian, breast, endometrial, colorectal and other Lynch-associated cancers across either parental lineage requires careful pedigree assessment.
Persistent abdominal distension, early satiety, pelvic pain, urinary change or postmenopausal bleeding requires symptom-led investigation even during hereditary-risk surveillance.
Investigation priorities
Define tumour types, ages, biological relationships and the maternal or paternal lineage before estimating carrier probability.
Management branches
A person is diagnosed with endometrial cancer, invasive epithelial ovarian cancer or another qualifying ovarian tumour.
- For endometrial cancer, initiate mismatch-repair immunohistochemistry and use MLH1 promoter hypermethylation or direct germline testing according to the protein-loss pattern.
- For qualifying ovarian cancer, offer informed genomic testing using the current NHS pathway, distinguishing tumour testing from constitutional testing.
- Document consent and results, act on treatment implications, refer complex or positive findings to genetics, and create a route for relatives to access cascade testing.