Genomics Toolkit: Colorectal

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.

• 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).

• 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.

• 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.

• 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.

• 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.

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.

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.

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.