On 11/17/23, I emailed my genetic counselor to check in on the status of my VUSes (variants of uncertain significance). I also wanted to give her an update on my own medical history, including last year's oophorectomy and the genetic testing results of some relatives. The last time I had contact with my genetic counselor was over 2 years ago, so I first checked online to make sure she's still a member of the Cancer Genetics team. I sent a brief message to just confirm that I was emailing the right person.
By 12/4/23, I hadn't gotten a response, so I followed up with another email to the same address. Since the first email had not been returned as undeliverable, I figured the address was still valid. I was polite and tried not to be pushy, since there was no urgency.
To review, I have 2 VUSes on the BRCA2 and PALB2 genes, both of which are linked to breast cancer and ovarian cancer. Originally, it was important to follow up on these VUSes because if one or the other turned out to be a pathogenic mutation, I'd be at increased risk for ovarian cancer and would want to consider getting my ovaries out. But since I ended up getting my ovaries out for other reasons, the status of the VUSes don't actually matter much for me anymore. Still, if either of the VUSes are ever re-classified as harmful, then that information would certainly be useful for my kids to know, especially my daughter.
Anyway, by 12/14/23, I still hadn't heard back, so I sent a message to the general Cancer Genetics email address. The very next day, my genetic counselor called me!
She apologized profusely for not responding earlier. She said she did most of the research into my VUSes on the day she received my email, but she also made inquiries and had to wait for responses. Then she just forgot to email me back. Not sure why my first follow-up email also managed to fall through the cracks, but it was yet another good reminder that a patient needs to be their own best advocate.
Later in the day, I logged into the online patient portal to see the genetic counselor's notes on our conversation, to make sure I didn't miss anything. This post includes information and quotes from both the phone call and her notes.
Back to the phone call. I actually have 4 VUSes total, but the other 2, on CDKN1C and MSH2, aren't on genes related to breast cancer, so mostly I've ignored them. My genetic counselor said the MSH2 gene is linked to a number of cancers, mostly colon cancer, but since it's still classified as a VUS, she's not worried about it. She didn't mention the CDKN1C VUS, and I didn't bother asking.
She explained that there's a clinical database called ClinVar where laboratories report their results. There were 4 laboratories that reported on my PALB2 variant, and all 4 labs continue to classify it as a VUS.
The BRCA2 variant, however, was more complicated. Of the 6 labs that have reported on my BRCA2 variant, 5 still classify it as a VUS. A 6th lab, however, now considers it pathogenic, meaning they think this variant is harmful and could cause cancer. But. "Unfortunately they did not submit any supporting evidence for this interpretation. Given this is a non-US based laboratory which is not CLIA-certified, it is difficult to assign any significance to this interpretation." Basically, there is no documentation on what kind of standards this lab uses, so there's no way to know what level of confidence to place on their report.
Notably, though, this 6th lab is in China. I remembered what my first oncologist said about race in clinical studies, how in the U.S. the vast majority of patients are white, so results may not apply well to me, a Chinese person. I asked the genetic counselor if she thinks the fact that this lab's data represents patients who are almost certainly all Chinese means I should put at least some weight on their results? She conceded that their data set probably includes more Chinese people than all U.S. labs combined, but with no way to assess the legitimacy of the lab's results, she advised going with the majority opinion.
Moreover, she said she reached out to another lab called Myriad Genetics, which has extensive experience with BRCA1 and BRCA2 genes. I don't understand why they weren't included in the list of labs reporting in ClinVar, but she said there's been a few recent publications referencing my specific variant, and still Myriad considers it a VUS, based on their own data studying this variant in 17 families. Essentially, they just haven't seen this variant tracking with an increased risk of cancer.
She also mentioned that my particular type of variant can be hard to understand, as it consists of just a single nucleotide change. If I'm reading my genetic testing results correctly, I think my BRCA2 gene has a "T" where there should be an "A". Apparently, the question that needs to be answered is, given this variation, is the gene still functional?
As for what all this means for me. She said that if the variant was reclassified as pathogenic by a reputable U.S. lab, we'd have a conversation about taking action. I asked her what kind of "action" would be recommended, and at the same time told her about my oophorectomy. I could actually hear the relief in her voice, she clearly considered this good news. Getting my ovaries out would be the most drastic action on the table, and since I already did that, it was basically one less thing to worry about.
We also talked about what a pathogenic BRCA2 mutation would mean for my daughter. She said my daughter would be recommended to start breast cancer screening at age 25, including yearly mammograms and yearly MRIs, offset so that imaging is done every 6 months. I did see a similar recommendation online, but also found a site that recommended starting the imaging at age 30. Whatever the age, it sounds so burdensome to me, I hope she doesn't have to start so young. When she's older, she'll have to decide for herself if she wants to get genetic testing done; if she doesn't have the same mutation, she could be spared some of that early imaging, but if she does have the mutation, it could introduce additional anxiety and fear.
If the variant remains a VUS, my genetic counselor said my daughter would be expected to start breast cancer screening 10 years before the age I was diagnosed. (I was diagnosed at age 43, but I found the lump at age 42.) This is the same recommendation my PCP gave me, though of course my daughter will have to discuss all this with her own healthcare providers when she's older.
Finally, we talked about the genetic testing of my relatives. There is no known cancer on my mother's side, but quite a few cases of cancer on my father's side. I had previously given her the genetic testing results of a paternal cousin who doesn't have cancer, and now gave her the results of 2 other paternal cousins, also without cancer. I'm not really sure how useful the results are, but I found it interesting that we don't have any overlapping VUSes. She said getting the results for my father and my one surviving aunt who had breast cancer would actually be very helpful. Specifically, she said my dad's results "will clarify whether either or both of these variants were paternally inherited... even if he does carry 1 or both of the variant it is not indicative of causation." Regarding my aunt, if she "does not carry either of these variants, that certainly suggest that either or both of these variants may not be the cause of early onset breast cancer in the family." In which case, even if my daughter did inherit the same VUSes, it might be less scary.
My genetic counselor said she would try to streamline the genetic testing process, so any relative of mine in the area who wants genetic testing just has to have a brief telehealth genetic counseling appointment with her, and she'd ship them a saliva kit, which they can do at home and then mail back the sample.
Phew. That's a lot of information. And a lot of uncertainty.
