Results: Patient with cancer and no identified constitutional (germline) pathogenic variant

A 49-year-old woman is diagnosed with triple-negative breast cancer. In her family, two paternal aunts and a cousin were diagnosed with breast cancer at young ages. She has two younger sisters who have never been diagnosed with cancer. Constitutional (germline) testing of a panel of breast cancer genes is undertaken, and the report states that no pathogenic variants have been identified.

When constitutional (germline) genomic testing is undertaken in a patient with cancer who has a positive family history and no pathogenic variants are identified, the likelihood that a pathogenic single gene change in the tested genes is responsible for their cancer is greatly reduced.

However, due to the current limitations of testing, a heritable genetic cause or underlying risk cannot be excluded. It may be that the type of testing that would identify their genetic risk factor is not yet available, or their genetic risk factor cannot be detected by current technology.

A negative genomic test result may have an impact on the patient’s treatment options: it can render them ineligible for certain targeted treatments, and may also influence the extent of surgery or application of radiotherapy they are offered.

Management of the current cancer

An uninformative constitutional (germline) genomic result should be considered in ongoing clinical management.

Management of the future cancer risk

• A negative result does not explain the cause of cancer in the family. While the cancer may have occurred by chance or due to environmental or lifestyle factors, it is still possible that there may be existing heritable monogenic risk factors that cannot be identified using current technology, or for which testing is not currently available. Alternatively there may be lower-risk genetic factors working in combination (such as polygenic risk) to increase this individual’s cancer risk.
• Further constitutional (germline) genomic testing may be available in a research setting.
• In this scenario, in addition to routine post-cancer surveillance as per local protocols, the patient may be eligible for additional cancer screening based on the family history of cancer.
• You should assess the family history based on current NICE guidance around screening, or refer the case to the local cancer family history service.

Management of the family’s risk

• In the absence of a confirmed heritable genetic risk factor for cancer, predictive genomic testing is not available for relatives.
• First-degree relatives should seek advice about additional cancer screening through their GP.
• If there is significant family history, other relatives affected with cancer may wish to seek genomic assessment through their GP or treatment team. It is possible that the patient in our scenario has a sporadic cancer (a so-called phenocopy), and that the family history of cancer is explained by a heritable genetic risk factor that she did not inherit.

For clinicians

• British Society of Gastroenterology: Guidelines for the management of hereditary colorectal cancer from the BSG /ACPGBI/UKCGG
• NICE: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer

For patients

• NHS England Genomics Education Programme: Let’s talk about… Possible results (video, two minutes 36 seconds)
• Target Ovarian Cancer: What do the results mean for me?