Lynch syndrome

Lynch Syndrome predisposes to colorectal, endometrial and a variety of other cancers. It is caused by inherited mutations in one of four DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. Inheritance is autosomal dominant, but with gene-dependent age-related penetrance, variable expressivity, and sex limitation. The prevalence of mutations causing LS due to each gene is about 1/1000, so total prevalence of LS may be up to 1/250, which makes LS probably the most common form of predisposition to cancer.


The InSiGHT database includes classifications of pathogenicity for MMR variants with evidential basis (variants and classifications alone are also shown on ClinVar). An explanation of the methodology can be found in Thompson BA, et al.  Nat Genet 2014.


The full spectrum of nonsense, frameshift, splice, missense and large deletions/rearrangements is seen. Large deletions involving EPCAM (adjoining MSH2) can cause a rare form of LS characterised by a predisposition largely to GI cancers. Constitutional methylation of the MLH1 promoter can also cause LS. This is usually sporadic and not heritable, but some cases have heritable chromosomal rearrangements that cause MLH1 promoter methylation, by involving the LRRFIP2 gene that adjoins MLH1.

Constitutional Mismatch Repair Disorder (CMMR-D) occurs in individuals who inherit pathogenic mutations in both alleles of the same MMR gene. They suffer from a ‘classical’ DNA repair disorder with, amongst other things, a high risk of haematological and CNS tumours at a young age, and multiple colorectal adenomas.

There is undoubtedly a spectrum of CMMR-D, as one hypomorphic PMS2 mutation found in the Arctic Inuit is present at a frequency of 1/16 and homozygotes may only present with colorectal cancer in their 30s.


The Prospective Lynch Syndrome Database (PLSD) now provides the most accurate estimates of cancer risks in LS, both in individuals who have yet to develop a cancer and those who have survived a cancer. An individual’s risks can be found according to their age, gender and the underlying gene.

Lynch syndrome-related tumours include:

  • Colon and rectal cancer
  • Endometrial cancer
  • Small intestine cancer (MSH2 & MLH1)
  • Hepato-biliary and pancreatic cancer (MSH2 & MLH1)
  • Gastric cancer (MSH2 & MLH1)
  • Ovarian non-serous cancer (MSH2 & MLH1)
  • Renal pelvis and ureter cancer (MSH2 & MSH6)
  • Bladder cancer(MSH2 & MSH6)
  • Sebaceous gland cancer (and adenoma – Muir-Torre syndrome)
  • Prostate cancer (MSH2)
  • Breast cancer (MLH1)
  • Central nervous system cancer

The risks associated with some EPCAM deletions appear not to be restricted to GI cancers.

Lifestyle and environmental influences

A number of factors modify the risks of cancer in LS:

Laboratory testing

Cancers due to LS are characterised by loss of MMR in their cells, which usually (but not invariably) manifests as microsatellite instability (MSI) and abnormality of MMR protein expression on immunohistochemistry (IHC). See: Canadian Agency for Drugs and Technologies in Health report and Frayling, IM and Arends MJ. ‘How can histopathologists help clinical genetics in the investigation of suspected hereditary gastrointestinal cancer?’ Diagnostic Histopathol 2015.

Also available are Best practice guidelines for LS laboratory testing, including constitutional and tumour tests, and External quality assurance (EQA) of MSI testing.

Note that MSI in rectal cancers is unusual, but when seen usually indicates LS. However, colon cancers may also lose MMR repair due to sporadic methylation of the MLH1 promotor, which is increasingly likely over the age of about 60y, hence the predictive value for LS of MSI in a colon cancer is age-dependent.


In sporadic colon cancers with MSI the presence of the BRAF V600E mutation is often, but not invariably found. However, it is not found in colon cancers due to LS.

MLH1 methylation

The MLH1 gene promoter is typically methylated in sporadic colon cancers with loss of MMR and MSI. A small proportion of cases is due to constitutional and potentially heritable methylation. Testing for MLH1 promotor methylation is an alternative to BRAF testing.


IHC to detect abnormality of MMR expression is a technique complementary to MSI, BRAF and MLH1 methylation testing. MMR IHC used for diagnostic purposes should only be performed with appropriate external quality assurance (see UK and NordiQC examples) and optimisation of staining protocols.

Interpretation of IHC findings

The earlier view that patterns of MMR IHC abnormality conformed to simple relationships to the underlying inherited genetic mutation is now known to be more complex. Some tumours acquire somatic mutations in MMR genes due to underlying mutations in other genes such as MUTYH, POLD1 etc and so they may appear to be due to LS when they are not, a phenomenon that has been termed Lynch-like Syndrome (LLS).

Systematic testing

There is a strong health-economic case for the systematic testing of cancers in order to find cases of LS. This now forms some countries’ national policies, for example Denmark and the UK.

Clinical management

Colonoscopic surveillance is the cornerstone of management, and is supported by a strong evidence base.  Prophylactic colectomy or extended resection for colorectal cancer can be considered, and there is evidence that aspirin has a chemopreventive effect. The current CAPP3 trial is aimed at identifying the optimal dose. MMR gene mutation appears to influence the effect of some chemotherapeutic agents, and should be taken into account.

Surveillance is also sometimes employed at other potential tumour sites, and prophylactic hysterectomy and oophorectomy should be considered in women who have completed their families. InSiGHT has raised concerns regarding recent recommendations for pancreatic surveillance.

Various good quality published guidelines are available for download below.

Support groups

There are now a number of support groups or other sources of informationfor patients and families with Lynch syndrome:

Content updated 16 July 2019