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Example clinical scenario

A 72-year-old man is diagnosed with inoperable intra-hepatic cholangiocarcinoma. There is no significant family history of cancer. You wish to undertake genomic testing and are considering which somatic (tumour) and/or constitutional (germline) tests are available and appropriate for him.

When to consider genomic testing

Somatic (tumour) testing

  • Somatic (tumour) testing should look for fusions involving NTRK1, NTRK2 and NTRK3, or rearrangements or fusions involving FGFR2.
    • Detection of structural variants in these genes may mean that the patient is eligible for treatment with an NTRK or FGFR inhibitor.
    • Entrectinib and larotrectinib are approved for treatment of NTRK fusion-positive tumours if the patient has no other satisfactory treatment options and has not previously received treatment with an NTRK inhibitor.
    • Pemigatinib is licenced by NICE for patients with an FGFR2 fusion or rearrangement who have progressed on at least one line of systemic therapy. Other FGFR2 fusion inhibitors may be available through clinical trials.
  • Assessment of mismatch repair proficiency may be undertaken by immunohistochemistry if Lynch syndrome is suspected, or to inform therapy decision-making. Microsatellite instability analysis can be completed where mismatch repair immunohistochemistry is not performed.
  • Testing for small variants in IDH1 can be performed if it may aid diagnosis and management. NICE has recently issued guidance recommending ivosidenib, a small molecule IDH1 inhibitor, for the treatment of locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 variant in adults after one or more systemic treatments.
  • In addition, all patients with solid tumours who have exhausted all standards-of-care testing and treatment are eligible for whole genome sequencing (WGS) in order to explore clinical trial options.
  • In the future, somatic (tumour) testing is likely to be available and expanded to include larger somatic gene panels; ultimately, paired somatic and constitutional (germline) WGS will be performed.

Constitutional (germline) testing

  • Patients presenting with cholangiocarcinoma are eligible for constitutional (germline) BAP1 single gene testing if they have a personal history of, or first-degree relative with, another BAP1-related tumour (such as uveal melanoma, cutaneous melanoma, basal cell cancer, BAP1-inactivated melanocytic tumours (BIMT), malignant mesothelioma (lung or peritoneal), renal cell carcinoma, meningioma, cholangiocarcinoma or hepatocellular carcinoma).
  • Rarely, cholangiocarcinoma may be associated with Lynch syndrome; constitutional (germline) testing should be considered if the personal or family history is consistent with Lynch syndrome or if the tumour demonstrates features of mismatch repair deficiency and/or microsatellite instability.
  • Patients who are due to receive fluoropyrimidine chemotherapy should have constitutional DPYD hotspot testing prior to commencement of the agent to investigate for variants that may impact the patient’s metabolism of the drugs.

What do you need to do?

  • Consult the National Genomic Test Directory. From here you can access:
    • the rare and inherited disease eligibility criteria for information about constitutional (germline) tests in patients with cancer and their associated eligibility criteria;
    • the test directory for rare and inherited disease, a spreadsheet of all available constitutional (germline) tests; and
    • the test directory for cancer, a spreadsheet of all available somatic (tumour) tests.
  • To find out which genes are included on different gene panels for constitutional (germline) testing, see the NHS Genomic Medicine Service Signed Off Panels Resource.
  • Cholangiocarcinoma patients are eligible for BAP1 constitutional (germline) testing if they meet the following criteria:
    • BAP1-deficient mesothelioma, or mesothelioma diagnosed under 50 years of age if BAP1 status is unknown;
    • BIMT, also known as BAPoma, atypical Spitz naevus, melanocytic BAP1-associated intradermal tumor or nevoid melanoma-like melanocytic proliferation;
    • Personal history of two or more BAP1-associated tumours, including cholangiocarcinoma)*; or
    • BAP1-associated tumour and a first-degree relative affected with a BAP1-associated tumour*.

* Excluding the combination of basal cell cancers and/or cutaneous melanomas alone, given their high frequency in the general population. BAP1-associated tumours include uveal melanoma, cutaneous melanoma, basal cell cancer, BIMT, malignant mesothelioma (lung or peritoneal), renal cell carcinoma, meningioma, cholangiocarcinoma and hepatocellular carcinoma.

  • Single gene testing of BAP1 is requested using the code R422 (single variant detection by sequencing and exon level copy number variant detection by multiplex ligation-dependent probe amplification or equivalent).
  • A record of discussion (RoD) form is required before any constitutional (germline) genomic testing is requested.
  • Constitutional (germline) testing of DPYD is requested using the code M220.3 (hotspot small variant detection). An RoD form is not required to request this test.
  • For DNA-based tests (all the above listed tests), an EDTA sample is required. Please refer to your local Genomic Laboratory Hub (GLH) for details of test request forms and where to send samples.
  • Somatic (tumour) tests for cholangiocarcinoma are requested using the following codes:
    • M220.1 Multi-target NGS panel for structural variant detection – NTRK1, NTRK2, NTRK3, FGFR2;
    • M220.5 Microsatellite instability testing; and
    • M220.6 Multi-target NGS panel for structural variant detection – IDH1.

These somatic (tumour) tests can all be performed on formalin-fixed tumour samples.

  • WGS of any solid tumour where the patient has exhausted all standards-of-care testing and treatment is requested using code M232. For WGS, you will require:
    •  access to a fresh tumour sample and a matched blood (EDTA) sample (WGS requires paired somatic (tumour) and constitutional (germline) DNA analysis); and
    • a completed RoD form.
  • Please discuss the case with your local GLH before submitting samples for WGS to confirm the local test pathway details.
  • 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


For patients

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  • Last reviewed: 05/02/2024
  • Next review due: 05/02/2025
  • Authors: Dr Sarah Howlett
  • Reviewers: Dr Ellen Copson, Beth Coad, Dr Terri McVeigh, Dr Justin Mencel