Unusual Symptoms

Doctor's File Notes May 3, 2017 Genetic Counseling Follow Up

Date of Service: May 3, 2017

Encounter Type: Follow-up Telephone Call

I had the pleasure of speaking with [patient] in our Cancer Genetics and Prevention Program today for genetic counseling.

Results of the most recent genetic testing are negative for known disease-causing mutations. See below for details.

Tests performed and Results:

1)Germline (Blood) Genetic Testing: A sample was previously sent to Invitae for genetic analysis of 42 known cancer predisposing genes. The following genes were evaluated for sequence changes and exonic deletions/duplications: APC, ATM, AXIN2, BARD1, BMPR1A,,, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, DICER1, EPCAM, GREM1, KIT, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PDGFRA, PMS2, POLD1, POLE, PTEN, RAD50, RAD51C, RAD51D, SDHA, SDHB, SDHC, SDHD, SMAD4, SMARCA4, STK11, TP53, TSC1, TSC2, VHL. The results of this testing are negative for known disease-causing variants, meaning no mutation was identified.

Colon Tumor Molecular Analysis: [Patient's] colon tumor was previously evaluated for a possible association with Lynch syndrome by screening for expression of the mismatch repair genes. His colon tumor showed loss of MLH1 and PMS2, raising the possibility of Lynch syndrome. However, approximately 80% of tumors with loss of MLH1 and PMS2 will be due to sporadic (NON-inherited) methylation of the MLH1 promoter in the tumor only. I ordered MLH1 promoter methylation analysis of his tumor, and the results indicate that his colon tumor did have sporadic loss of MLH1 due to non-inherited methylation of the MLH1 promoter. This means that the MLOH1 gene was permanently turned off in his colon tumor, but this was only present in the colon cancer cells and is not an inherited situation. He does not have Lynch syndrome.

Comments and limitations:

The only finding on this test was a "variant of uncertain significance" (VUS) in the AXIN2 gene called c.251C>G. The result means that [patient] has a form of this gene that differs from the typical form of this gene, and there is not enough information to determine whether it increases the chances of developing cancer. The majority of variants will be reclassified as polymorphisms, meaning that they are likely to represent normal human variation. Clinical management and medical decisions should be based on personal and family history and not on the presence of a VUS. This particular gene, AXIN2, is associated with a condition that results in missing teeth (typically 6 or more, sparse hair, and colorectal polyps and cancer., [Patient] reports he has all of his teeth, and still has a full head of hair at age 75. It is extremely unlikely that this variant has any clinical significance. I instructed [patient] to ignore it. Research efforts to reclassify variants are ongoing, and [patient] will be notified if this variant is reclassified in the future.

Interpretations:

This result significantly reduces the chances that [patient] has an inherited predisposition to cancer. In particular, Lynch syndrome has been ruled out, which is the most common cause of colorectal cancer that runs in families. We have also ruled out BRCA-associated prostate cancer. However, {patient] still has a personal and/or family history of cancer that is not explained by current genetic testing. We discussed some possible interpretations.

Based on his personal and family history, the most likely explanation for the patients personal and family history of cancer is multifactorial, due to a combination of genetic and non-genetic (age, environmental, hormonal, etc.) risk factors that act together. In the case of multifactorial cancer, there may be a moderately increased risk for cancer. Both his mother and maternal aunt had colon cancer, and therefore we know he is at increased risk for a second primary colorectal cancer. His brother is also at increased risk for colon cancer. Management for colorectal cancer risk is therefore altered to address these increased risks (see below).

Cancer Screening and Prevention:

[Patient] should continue to seek treatment and surveillance for his past diagnoses of cancer based on the recommendations of his health care providers. In particular annual colonoscopy, ongoing PSA monitoring, and check ups of the esophagus. I reviewed his most recent screening and he is up to date. He has a very good understanding of his surveillance plan.

Other at-risk family members should discuss recommendations with their physicians in the context of their personal risk factors. I recommend that his brother have colonoscopy every 3-5 years and annual PSA testing.

Counseling Summary:

I spoke with [patient] for cancer risk assessment and to discuss the results of generic testing that were negative. We reviewed the variant of unknown significance in the AXIN2 gene, and that we can ignore this, as he does not have clinical features consistent with a mutation in this gene. I also discussed the potential emotional impact of cancer risk and genetic testing. I recommended that the patient discuss this information and our recommendations with his relatives, in particular his brother.

[Patient] previously enrolled in the Cancer Genetics and Prevention Program long-term follow-up registry.

I discussed the fact that the assessment and recommendations are based on information available at this time. I asked [patient] to re-contact the Cancer Genetics and Prevention Program periodically to inquire about possible advances in cancer genetics that may be relevant to his family., I also request he inform the program of changes in the family history, such as new diagnoses of cancer, as these could significantly alter his assessment and recommendations. Please do not hesitate to call me with any questions about this information.