Presentation: Patient with a family history suggestive of Lynch syndrome

A 24-year-old asymptomatic man has been to his GP to enquire about genomic testing. His father has recently been diagnosed with an MLH1/PMS2-deficient colorectal cancer, with subsequent genomic tests confirming that his father has Lynch syndrome with an MLH1 pathogenic variant.

• Predictive testing should be considered for first-degree relatives of a person with a confirmed genetic diagnosis of Lynch syndrome.
  • First-degree relatives have a 50% chance of having the condition, thus are eligible for targeted genomic testing.
• Testing should also be considered for asymptomatic ‘unaffected’ individuals with:
  • a first-degree relative with a Lynch-related cancer;
  • a positive family history according to the modified Amsterdam criteria (see below); and
  • where testing is not possible in the affected person (see below).
• An unaffected individual is eligible for germline genomic testing through the National Genomic Test Directory when:
  • a first-degree relative is affected with Lynch-related cancer;
  • there is a family history of colorectal cancer/Lynch-related cancers that meets Amsterdam criteria (≥3 cases over ≥2 generations with ≥1 case affected <50 years of age);
  • tumour sample analysis has been attempted for an affected family member and is not possible, failed, is indeterminate or indicates MMR deficiency (via immunohistochemistry (IHC) or microsatellite instability (MSI));
  • somatic sequencing is not possible, or failed; and
  • there is no living affected individual is available for genomic testing.
• Lynch-related cancers comprise: colorectal cancer, endometrial cancer, epithelial ovarian cancer, ureteric cancer, transitional cell cancer of renal pelvis, cholangiocarcinoma, small bowel cancer, glioblastoma, endocervical cancer, multiple sebaceous tumours, prostate cancer, gastric cancer and pancreatic cancer.
• Current guidance suggests that children of individuals with Lynch syndrome should not be offered genomic testing in childhood. They can be referred to the clinical genetics service from 18 years of age.
• For detailed guidance on colonoscopic surveillance for those with a strong family history of colorectal cancer or first-degree relatives of patients with Lynch-like syndrome, please refer to these guidelines for the management of hereditary colorectal cancer.

• Take a family history of cancers going back three or more generations and draw a complete genetic pedigree. Identify those with a confirmed genetic diagnosis of Lynch syndrome and those with a cancer diagnosis.
• Request a copy of the genetic report of the closest relative with a confirmed diagnosis of Lynch syndrome.
• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed-Off Panels Resource.
• If eligible, refer your patient to the clinical genetics service for genetic counselling to discuss the implications of predictive testing.
• Genomic testing of unaffected individuals can only be carried out by the clinical genetics service. For reference, the relevant tests are:
  • R242 Predictive testing for known familial variant(s): This is predictive or targeted variant testing. First-degree relatives will undergo targeted testing of the known genetic variant identified in their relative.
  • R210 Inherited MMR deficiency (Lynch syndrome): This is a small gene panel specific to Lynch syndrome. It is to be used for people who have a first-degree relative with a Lynch-related cancer, who meet the modified Amsterdam family history criteria, and where testing is not possible in the affected individual.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Cancer Genetics Group: UKCGG leaflets and guidelines (see Lynch syndrome)
• NHS England: National Genomic Test Directory
• RM Partners West London Cancer Alliance: Lynch Syndrome online training for MDTs: Option 1
• RM Partners West London Cancer Alliance: Lynch syndrome online training for primary care clinicians

References:

• Monahan KJ, Bradshaw N, Dolwani S and others. ‘Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)‘. Gut 2020: volume 69, pages 411–444. DOI: 10.1136/gutjnl-2019-319915

For patients

• The Fruit Fly Collective (Tools to support people with Lynch syndrome explain their diagnosis to their children)
• Genetic Alliance UK
• Lynch Syndrome UK