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Clinical features

  • Individuals with Lynch syndrome have an increased lifetime risk of a variety of cancers, most commonly colorectal cancer or endometrial cancer, as well as ovarian, pancreaticobiliary, gastric, small intestinal, brain, urinary tract, skin and other cancers. The exact risks depend on the underlying genotype.
  • Affected individuals usually have a family history of bowel cancer and other Lynch syndrome-related cancers.
  • Cancers associated with Lynch syndrome are typically mismatch repair (MMR) deficient and/or demonstrate microsatellite instability (MSI).

The genetics of Lynch syndrome


  • Lynch syndrome arises from a pathogenic constitutional (germline) variant of one of the genes involved in DNA mismatch repair: MLH1, MSH2, MSH6, PMS2, or from inactivation of MSH2 owing to deletion in the neighbouring EPCAM gene.
  • Rarely, Lynch syndrome may be caused by constitutional hypermethylation of the MLH1 promoter, leading to inactivation of MLH1.

Inheritance and genomic counselling

  • Lynch syndrome is an autosomal dominant condition, so that each child (son or daughter) and each sibling (brother or sister) of an affected individual has a 50% (1-in-2) chance of inheriting the condition.

Diagnosis and management of Lynch syndrome


  • Lynch syndrome may be suspected from a family history of bowel cancer and other Lynch syndrome-related cancers, triggering genomic testing in the family.
  • NICE guidelines recommend screening all colorectal cancers and all endometrial cancers for Lynch syndrome at first diagnosis.
  • Colorectal cancers may be screened for Lynch syndrome using either:
    • immunohistochemistry (IHC) to identify loss of expression of MMR proteins; or
    • MSI testing.
  • MSI testing is less sensitive in endometrial cancer, so these tumours should be screened for Lynch syndrome using IHC testing to check for MMR deficiency.
  • Genomic testing for underlying constitutional (germline) MMR gene variants is guided by the results of MSI and/or IHC testing.
  • Gene panel tests are available for the MMR genes and/or other high and medium penetrance colorectal cancer predisposition genes.


  • Daily aspirin has been shown to reduce the risk of colorectal cancer and certain other cancers in Lynch syndrome. The optimal dose remains to be established (see the ongoing CAPP3 study). Current UK Cancer Genetics Group guidelines recommend a dose of 150mg once daily, but individuals weighing over 70kg may benefit from a higher dose.
  • Surveillance for colorectal cancer by screening colonoscopy every two years (from age 25 for MLH1/MSH2 and age 35 for MSH6/PMS2 mutation carriers).
  • Screening for extracolonic cancers has not been shown to be effective, and is not recommended outside of research studies. The following should be considered to reduce cancer risk:
    • Screening for and eradication of Helicobacter pylori as indicated, to reduce stomach cancer risk. This is recommended before commencing aspirin chemoprophylaxis.
    • Women who have completed their family may consider risk-reducing surgery to remove the uterus, fallopian tubes +/- ovaries, after the age of 35. Hormone replacement therapy is usually recommended after risk-reducing bilateral salpingo-oophorectomy to offset negative impact of premature menopause, up until the time at which natural menopause would be expected to occur.
    • Prompt investigation of any symptoms (gynaecological, urinary, gastrointestinal, dermatological and so on).
  • Referral of affected patients to clinical genetics should be arranged to discuss onward management, family planning implications, and cascade testing of relatives at risk.

Family planning implications

The Human Fertilisation and Embryology Authority has approved the use of pre-implantation genomic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one/both of the intended parents is a carrier of a likely pathogenic or pathogenic variant in a MMR gene associated with Lynch syndrome. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children later in life.

Tagged: Endometrial cancer, HNPCC, Colorectal cancer

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2024
  • Authors: Dr Amy Frost
  • Reviewers: Dr Ellen Copson, Dr Terri McVeigh