Case: Identify patients for germline testing

Older Caucasian woman

MV is a 77 year old woman recently diagnosed with stage IIIB colorectal cancer. At diagnosis, the patient had two synchronous right colon adenocarcinomas discovered during screening colonoscopy, and was treated surgically with right hemicolectomy. One of 24 lymph nodes was positive.  She is currently undergoing adjuvant therapy. Her family history is significant for ovarian and stomach cancer in maternal relatives; she has no family history of colorectal cancer.  Genomic tumor testing was ordered to determine possibility for future therapy, if needed.

Results from ActionSeq:

  • Actionable variants: ARID1A P224Rfs*8, TP53 R175H
  • VUSs in CDK12, GLI1, PIK3CA, RNF43, TGFBR2
  • No actionable fusions detected

Should MV be referred to genetics for consideration of germline testing?

  1. No, given her age there is no indication for germline testing
  2. No, no variants in genes associated with hereditary forms of colon cancer were found
  3. Yes, her personal and family history are sufficient to refer her.

See the answer

The correct answer is C. Yes, her personal and family history is sufficient to refer her to genetics.

In this case, the decision about referral for germline testing is based on MV’s personal and family history, not on the results from tumor testing. MV’s personal history of having two right-sided synchronous colon cancers is suspicious for Lynch syndrome. Furthermore, in this case, her personal and family history of colon, ovarian, and stomach cancers, is significant because these are classic Lynch syndrome component tumors.

It is important to collect sufficient information about the family history in order to assess genetic risk. MV’s family history report does not include who in the family was affected with stomach and ovarian cancers, or at what age they were diagnosed, which can help clarify whether or not MV is truly at risk for a hereditary cancer susceptibility disorder. In addition to identifying the cancer types in the family, ask how the affected individuals are related to your patient (e.g., sister, maternal grandfather, etc.) and the age at which the relative was initially diagnosed with cancer. In this case, it is also important to assess the patient and family for non-cancer risk factors, including the presence of multiple colon polyps over a lifetime. Most pertinent to this case, NCCN recommends that any individual “with colorectal or endometrial cancer and >= 2 first-degree or second-degree relatives* with a Lynch syndrome-related cancer, regardless of age” be evaluated for Lynch syndrome. MV meets this criterion. Furthermore, her personal history of synchronous colon cancers meets NCCN referral criteria alone.

Genomic tumor testing should not be used to diagnose patients with a hereditary cancer syndrome. Tumor-only tests, such as ActionSeq, that assess only the cancer tissue for variants, do not test normal (germline) cells. Tests that assess both tumor and normal tissue (tumor-normal testing) may or may not report variants in the germline. In addition, tumor tests may not report on all variants associated with hereditary cancer syndromes if they are not associated with targeted treatments and/or the test lacks sensitivity to detect the variant. Relevant to MV’s case, at the time it was done, ActionSeq included testing for 4 of the 6 genes associated with Lynch syndrome. Therefore, a negative tumor result (or one that does not include a pathogenic germline variant) reduces but does not rule out this condition.

In some cases, results from genomic tumor testing may help determine which patients should be referred for further evaluation. Results that indicate a pathogenic variant found in a gene associated with a hereditary cancer syndrome that conforms to the patient’s personal or family history (e.g., BRCA1 variant in a woman with ovarian cancer), a known founder mutation (a variant common in individuals in a specific population such as those with Ashkenazi Jewish or French-Canadian descent), or the presence of many variants all warrant further evaluation to determine whether germline testing is appropriate.

In all cases, regardless of genomic tumor testing results, if a patient meets germline testing criteria, he or she should be referred.

* first-degree relatives are parents, children, and siblings; second-degree relatives are half-siblings, grandparents, aunts, uncles, and grandchildren.

Learn more


This resource was developed as part of the Maine Cancer Genomics Initiative (MCGI) and is supported by The Harold Alfond Foundation and The Jackson Laboratory.