About the toolkit

From niche to necessity, genomic testing is now ready for rollout within the NHS. We want to help healthcare professionals deliver a gold standard of care to patients.

Genomics is rapidly becoming an integral part of cancer care and its clinical significance will only increase in time, transitioning into a central pillar of routine cancer treatment and prevention. Macmillan understands the importance of supporting both those living with and beyond cancer, but also the people who make that happen: the healthcare professionals.

This area of the toolkit will cover a specific tumour site: colorectal.

A headshot of Antigone Johnstone-Burt, Genomics Clinical Fellow at Macmillan. She is wearing a blue NHS uniform and her brown hair is tied back. She is smiling at the camera.

About the author

Reviewers and contributors:

  • Dr Claire Taylor, MBE, PhD, RGN. Chief Nursing Officer, Macmillan Cancer Support
  • Laura Monje-Garcia, National Lead Nurse for the Lynch Syndrome Project, Nurse Practitioner, St Mark’s Hospital
  • Victoria Cuthill, Nurse Consultant, St Mark’s Hospital.

Mainstreaming criteria

Lynch

These are the R210 criteria for inherited MMR deficiency.

All new diagnoses of colorectal and endometrial cancers should have tumour MSI/IHC testing completed.

This may include BRAF testing in MLH1 deficient colorectal cancers and MLH1 hypermethylation testing in BRAF negative colorectal cancers and all MLH1 deficient uterine cancers. MLH1 hypermethylation testing is included on the Cancer Test Directory under M1.5.

Testing of unaffected individuals can only be carried out by Clinical Genetics Services.

Please refer to the National Genomic Test Directory for other tests related to Colorectal Cancer.

  • 1. Criteria for germline testing an affected individual

    A dMMR tumour where additional testing results suggest Lynch Syndrome:

    • BRAF testing in MLH1 deficient colorectal cancers
    • MLH1 hypermethylation testing in BRAF negative colorectal cancers
    • ALL MLH1 deficient uterine cancers.

    A positive family history of modified Amsterdam Criteria (regardless of dMMR tumour status).

    Personal or family history suggestive of CMMRD (Constitutional Mismatch Repair Deficiency) with Wimmer score of 3 or more.

  • 2. Criteria for MSI/IHC testing on a stored tumour sample prior to germline testing
    • Personal/family history of colorectal cancers reaching Modified Amsterdam Criteria (≥ 3 cases of Lynch related cancer over ≥2 generations with ≥1 case diagnosed under 50yrs.
    • Any lynch-related cancer* under 50 years (excluding isolated pancreas, prostate or gastric cancers).
    • Two Lynch-related cancers (any age, if one is colorectal or endometrial).
    • Lynch-related cancer and 1 or more first degree relative has Lynch-related cancer (both occurred 60 years or less, one is colorectal or endometrial).
    • Lynch-related cancer and 2 or more relatives (first / second / third degree relatives) have Lynch-related cancer (all occurring ≤75years, one is colorectal or endometrial).
    • Lynch-related cancer and 3 or more relatives (first / second / third degree relatives) have Lynch-related cancer (occurring any age, one is colorectal or endometrial).
  • 3. Criteria for somatic (tumour) Lynch syndrome panel testing
    • Individual has colorectal or endometrial cancer with a dMMR tumour with normal BRAF and MLH1 hypermethylation analysis AND germline testing did not reveal a pathogenic mutation.
    • Personal/family pattern of disease whereby demonstration of acquired MMR mutations (and therefore exclusion of constitutional MMR abnormality) enables downscaling of surveillance.
    • Deceased affected individual with colorectal or endometrial cancer ≤60 years AND tumour featuring high/intermediate MSI or loss of staining of MMR protein(s) on IHC, AND one first degree relative with Lynch-related cancer ≤60 AND no living affected individual is available for genetic testing.
  • 4. Clinical criteria for germline testing in an unaffected individual (see note on testing)
    • First degree relative affected with Lynch-related cancer, AND
    • Family history of colorectal cancer/Lynch-related cancers reaches Amsterdam Criteria (≥3 cases over ≥2 generations with ≥1 case affected <50 years) AND
    • Tumour sample analysis from affected family member has been attempted and is not possible, failed, indeterminate or indicates MMR deficiency (via IHC or MSI), AND
    • Somatic sequencing is not possible, or failed, AND
    • No living affected individual is available for genetic testing.

*Lynch related cancers include:

  1. Colorectal cancer
  2. Endometrial cancer
  3. Epithelial ovarian cancer
  4. Uretic cancer
  5. Transitional cell cancer of renal pelvis
  6. Cholangiocarcinoma
  7. Small bowel cancer
  8. Glioblastoma
  9. Endocervical cancer
  10. Multiple sebaceous tumours
  11. Prostate
  12. Gastric
  13. Pancreas.

Inherited polyposis and early onset CRC

These are the R211 panel inclusion criteria. The individual has colorectal polyps and meets one or more of the following criteria.

Please refer to the National Genomic Test Directory for other tests related to colorectal cancer (see document titled rare and inherited disease eligibility criteria). 

Please note:

  • Inherited polyposis somatic test should be used if no living affected individual is available for germline testing, no germline DNA sample has been stored from a deceased affected individual, and a molecular diagnosis is required to advise living relatives
  • M1 Colorectal carcinoma test should be used for somatic testing.

The criteria

  • Any colorectal cancer diagnosis under 40yrs.
  • 5 or more adenomatous polyps and colorectal cancer.
  • 5 or more adenomatous polyps under 40yrs.
  • 10 or more adenomatous polyps under 60yrs.
  • 20 or more adenomatous polyps aged 60yrs or over.
  • 5 or more adenomatous polyps (under 60yrs) AND first degree relative with 5 or more adenomatous polyps or colorectal cancer (under 60yrs).
  • Serrated polyposis
    • 5 or more serrated lesions/polyps near the rectum, 5mm+ in size with at least two being 10mm in size.
    • 20 or more serrated lesions/polyps of any size in any part of the large bowel with at least 5 being proximal to the rectum.
  • Hamartomatous polyposis syndromes
    • 5 or more harmartomatous polyps in the colorectum.
    • 2 or more harmartomatous polyps throughout the GI tract.
    • 1 or more harmartomatous polyp and a first/second degree relative with harmartomatous polyps.

Preimplantation genetic testing is available to potential parents who are at risk of passing an inherited genetic condition down to their children.

It is an IVF treatment that identifies the associated genetic change in embryos so that only the embryos that are clear of these pathogenic changes may be implanted.

The process can take up to a year following initial consultation with a genetic counsellor.

Couples are eligible for treatment via the NHS if they meet certain criteria. 

Further reading:

List of all inherited conditions that have been approved by the Human Fertilisation & Embryology Authority

More detailed information on Preimplantation Genetic Testing for healthcare professional on NHS.UK

Patient pathways

Every unit will have variations on how patients navigate their pathway.

Please see below some examples of how genomic mainstreaming can fit into Secondary Care based on current clinical practice in NHS Hospitals.

Colorectal cancer pathway for tumour tissue testing [PDF]

Royal Marsden Partners have developed a lynch syndrome early diagnosis pathway for colorectal cancers, showing how genomic mainstreaming can fit into Secondary Care based on current clinical practice in NHS Hospitals. Learn more about the project on the Royal Marsden Partners website.

Secondary Care

The options for tumour tissue testing include:

  • Option 1: Immunohistochemistry
  • Option 2: Microsatellite instability

Predictive

  • Testing an asymptomatic adult who is related to a person with a diagnosed Lynch Syndrome pathogenic variant.
  • Not available to children, due to adult-onset disease associated with LS.

Diagnostic

  • Testing of a patient’s germline to identify a pathogenic variant in one of the mismatch repair genes.
  • For all colorectal and endometrial cancer patients.
  • Follows an abnormal result from the test on tissue sample (abnormal MMR shown on IHC or MSI).
  • Offered to people with a history of LS tumours and a confirmed pathogenic variant in the family.

Cascade

  • Aims to find relatives who carry a pathogenic variant for Lynch Syndrome before they develop a cancer.
  • In the UK, patients are relied upon to contact possibly affected relatives.
  • Georgiou et al, suggest a more novel approach of utilising healthcare providers, with patient consent to lead cascade testing.

Clinical documents

NHS Genomic Medicine Service Test Order forms

Visit your region for local Non-Whole Genome Sequencing (WGS) form:

Letters of results

The following examples have been created by the RM Partners West London Cancer Alliance to give an idea of what to write in the genetic results letter.

  • Positive: Pathogenic Variant Identified

    The result of your genetic test for Lynch syndrome is now available. A genetic change was identified in a gene called MLH1. This genetic change is considered pathogenic (disease-causing). This confirms your diagnosis of Lynch syndrome, and gives us an explanation of why you developed bowel cancer. Your medical team will use this information in their medical management decisions, it gives you access to personalised therapies, and a personalised surveillance programme.

    This also help us to be able to offer your first degree relatives (parents, siblings, and children) a genetic blood test as they have a 50% of having this genetic change, and therefore, a higher risk of developing bowel or other cancers.

    For this reason, we have referred you to your local clinical genetics department who will give you an appointment to discuss your result in more detail with you, and facilitate genetic testing and surveillance for your first degree relatives. You should receive an appointment with them over the post in few weeks’ time.

    Please continue your follow up with Dr [Oncologist]. Please do not hesitate to contact me should you have any clinical questions, or any queries about this result.

  • Negative: Pathogenic Variant not identified

    The results of your genetic testing to see if you have any genetic changes in the genes associated with Lynch syndrome is now available. Analysis shows that you do not have any genetic changes in these genes. A negative result does not change your diagnosis, nor does it rule out an inherited condition and we may need to look at other genes.

    We have now referred you to your local clinical genetics department so they can ‘virtually' assess if any further testing is available. They may give you an appointment if they can offer you further testing, or surveillance recommendations for your family.

    Please continue your follow up with Dr [Oncologist]. Please do not hesitate to contact me should you have any clinical questions.

  • Uncertain result: Variant of Unknown Significance

    The results of your genetic test to see if you have any genetic changes in the genes associated with Lynch syndrome are now available. Analysis has revealed a variant of unknown clinical significance in the MLH1 gene. What this means is that we are not sure whether this genetic change is disease-causing (pathogenic), or part of your normal DNA variability that do not cause disease. For this reason, we are unsure that this could explain why you developed colorectal cancer, and we cannot use it to offer genetic testing to your family members.

    We have now referred you to your local clinical genetics department so they can ‘virtually' assess if any further testing is available. They may give you an appointment if they can offer you further testing, or surveillance recommendations for your family.

Patient information and support

Lynch Syndrome

Key risk factors for hereditary bowel cancer

  • Diagnosed with bowel cancer before the age of 50 years
  • Bowel cancer that has been screened and tested positive for Lynch syndrome (an abnormal IHC/MSI)
  • Multiple bowel polyps
  • Two or more close relatives diagnosed with bowel or associated cancers like endometrial cancer
  • A close relative diagnosed with bowel cancer before the age of 50 years
  • More than one primary cancer (related) like bowel and womb in an individual. 

Educational resources

This section of the toolkit covers key points around counselling, consent and results. In addition, a list of frequently asked questions are answered.

Colorectal cancer susceptibility genes

This section of the toolkit covers the colorectal cancers susceptibility genes.


Adenomatous Polyposis Syndrome:

  • APC (dominant inheritance)
  • MUTYH (recessive inheritance)

Lynch Syndrome:

  • MLH1
  • MSH2
  • MSH6
  • PMS2

Hamartomatous Polyposis Syndrome:

  • SMAD4
  • BMPR1A
  • STK11
  • PTEN

Clinic set-up and discussion tool

Most teams find it takes around 3 months to set-up their services. This section of the toolkit provides some guidance to help think about what is needed during the set-up process.

GMSA map

A map to highlight the boundaries when professionals are selecting their regional GMSA website.

Visit your regional Genomic Medicine Service Alliance (GMSA) website: