Colorectal Cancer Risk Assessment and Consideration of Genetic Testing

The frequency of an individual who is affected with a colorectal cancer having a germline MMR mutation is 2-4%.

The following people warrant a referral to the service:


  • An individual at 25% or 50% risk of inheriting a MMR gene fault previously identified in their family.
  • An individual with a strong family history of cancers associated with mismatch repair gene faults.

Affected Individuals
This is based on the outcome of clinical investigations performed on tumour tissue. These are:

  • Immunohistochemistry (IHC) for MMR proteins expressed in tumour tissue.
  • Microsatellite Instability (MSI) testing of tumour tissue
  • BRAF V600E testing of MLH1 negative tumours
  • MLH1 promoter methylation studies
  • Promoter methylation studies of other MMR genes

The above tumour studies guide which MMR gene is tested.

Referral Guidelines

  • Families that meet Amsterdam II criteria (see below)
  • Mismatch Repair deficient cancer if;

Colorectal cancer

  • There is loss of any MMR protein on IHC
  • Loss of MLH1 and/or PMS2 on IHC with no BRAF mutation and/or normal MLH1 promoter methylation studies
  • Loss of MSH2 and MSH6 proteins
  • Loss of MSH6 protein only
  • Loss of PMS2 protein only

Testing is NOT Indicated when

  • An individual has a colorectal cancer >60 with no family history of Lynch Syndrome even though they have loss of MLH1/PMS2 but do have a BRAF mutation or tumour MLH1 promoter methylation
  • An individual with one sebaceous adenoma with any loss of MMR gene proteins in that adenoma but no family history of colorectal cancer

Genetic Testing for Lynch Syndrome is complex and dependent on tumour characteristics. It may also require different testing techniques, if the affected individual fulfils testing criteria. Please refer to diagnostic vs
predictive testing. Testing an unaffected individual will not necessarily rule out the need for surveillance.

Amsterdam II Criteria
The Amsterdam II criteria defines the minimum requirements for a clinical diagnosis of Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC).

There should be at least three relatives with a Lynch/HNPCC-associated cancer (cancer of the colorectum, endometrium, small bowel, ureter or renal pelvis) and..

  • One should be a rest-degree relative to the other two
  • At least two successive generations should be affected
  • At least one should be diagnosed before age 50
  • Familial adenomatous polyposis should be excluded
  • Tumors should be verified by pathological examination