Variants of Unknown Significance on Genetic Tests

I have a VUS, too. It didn't change my treatment plan but I think I do feel a bit better knowing I had a BMX, just in case. My genetic test was done by GeneDx and they don't list the Polyphen or SIFT results, but doing a search by the mutation itself gave me the result. Polyphen: Possibly damaging, and SIFT: deleterious. There's also another rating listed, UMD-predictor: 80 (pathogenous).

Dear kleigh1, Welcome. We hope that you will find some answers and information here. You have joined a well informed and supportive community. We are glad that you reached out. For you and anyone else who is reading here we have posted a survey:

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The Mods

I might do that hopeful....

Kleigh1:

Your question is a good one. I agree that you would do well to obtain a second opinion along the lines suggested by ShetlandPony.

If you did not receive Genetic Counseling services upon receipt of your test results, as part of your second opinion, please also arrange for Genetic Counseling to ensure that you understand the nature of your specific mutation.

You said you have a "variant of unknown significance" or "VUS" for BRCA2. The definition of "VUS" can vary, so you should obtain a complete copy of your test results for your records, determine how "VUS" was defined by your testing company, and see what information they provided to you about the specific "VUS" identified.

The level of risk associated with uncommon or never-before-seen variants in a gene often has not been determined, and so the risk is therefore "unknown". In general, a VUS might be pathogenic or not pathogenic. It is not known which it is. It could be pathogenic (harmful) and confer a risk of cancer, and if so, the actual amount of risk conferred may be relatively lower, the same, or higher than the risk associated with other known pathogenic mutations in the same gene . . . OR it could be non-pathogenic with no material affect on risk of cancer. Again, it is not known at this time whether it is either okay or bad to have it. Per NCCN guidelines on Genetic/Familial High-Risk Assessment: Breast and Ovarian (Professional Version 1.2016):

"Another counseling dilemma is posed by the finding of a variant of unknown significance (VUS) (see Table 2), a genetic alteration that may actually represent a benign polymorphism [genetic variation] unrelated to an increased breast cancer risk or may indicate an increased breast cancer risk. The individual must be counseled in such a situation, because additional information about that specific mutation will be needed before its significance can be understood."

It is my layperson's understanding that in the more typical case (i.e., absent significantly concerning personal medical and/or family history which could separately warrant action), a true "variant of unknown significance" is not "actionable" and prophylactic surgeries may not be warranted. This is because a "VUS" might not be pathogenic at all. It may later be determined that the VUS is not harmful, so prophylactic surgery may not be needed. Unfortunately, until additional information becomes available so that the VUS can be "re-classified" (e.g., as benign or pathogenic), the difficulty is that the actual situation is not clear (one may or may not be incurring risk). This complexity is also why Genetic Counseling is recommended under current guidelines.

Different testing companies may have more or less information about specific variants, and this is not always publicly available. On occasion, a more experienced team at a center of excellence may sometimes have access to some additional information about a particular VUS from experience with other patients or testing services.

Those interested in the guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian (Professional Version 1.2016) should obtain the latest update from www.nccn.org (free with Registration). The charts up front have been updated, and the text in the second half is under revision. They can be difficult to understand, and you should always confirm your understanding with a professional familiar with the guidelines by the nature of their practice (i.e., not your ordinary OB/GYN).

The above is for information only, and may contain errors of fact or understanding. Please confirm all information above with an expert professional in light of your specific test results.

BarredOwl

Experts aren't very helpful when you have a variation of unknown significance. I have a BRCA 1 variation and nobody has a clue whether it amounts to anything apart from saying "well you have bc so it may have been the cause". 

Hi:

Your experience illustrates the point: The fact that experts may know nothing about a variant of unknown significance is exactly why a second opinion is in order for kleigh1.

For the reasons noted in my post above, if a person with a VUS has received advice to pursue prophylactic surgery, an expert second opinion is advisable and may indeed be illuminating, because it may not confirm the advice received.

I should add that there is a second guideline available at www.NCCN.org, also recently updated, entitled "Breast Cancer Risk Reduction" (Version 1.2016). Because any particular recommendation may or may not apply in the particular case, it is important to always confirm your understanding with a professional familiar with the guidelines by the nature of their practice and familiar with the details of your situation.

As I mentioned above, the estimated lifetime risk associated with a known pathogenic mutation in any particular gene, such as BRCA2, may vary depending on the particular pathogenic mutation and on the particular type of cancer in question. With regard to ovarian cancer, per the NCCN guideline "Breast Cancer Risk Reduction" (Version 1.2016) notes (BRCA2 range in bold):

"Although the risk for ovarian cancer is lower than the risk for breast cancer in a BRCA1/2 mutation carrier (eg, estimated lifetime risks of 36%–46% and 10%– 27% in BRCA1 and BRCA2 mutation carriers, respectively (89,99-102)."

The lifetime risk, IF ANY, associated with a VUS is unknown. This concept is a challenge for patients and clinicians alike, who very naturally tend to attribute a cancer diagnosis to a VUS, despite the possibility that the VUS may possibly be a neutral variant (also called "nonpathogenic," "of no clinical significance," or "benign").

Robson (2015) ASCO Policy Statement: "ASCO Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility": http://ascopubs.org/doi/abs/10.1200/JCO.2015.63.0996

"VUSs are alterations in the genetic code that may or may not affect the function of the protein. VUSs are more common in broad-panel testing both because of the number of genes tested and because of the limited understanding of the range of normal variation in some of these genes. It is usually inappropriate to change the clinical management of a patient based on the finding of a VUS. Unfortunately, there is some evidence that clinicians may overinterpret VUSs and make recommendations that should be reserved for individuals with clearly deleterious mutations."

For more information about variants of unknown significance and the complex issues and challenges they present in clinical practice, these articles in the BRCA area can be instructive. I would venture to say that many everyday medical professionals are not familiar with this body of literature.

Eccles ENIGMA (2015) pdf: http://annonc.oxfordjournals.org/content/26/10/205...

Cheon (2014): http://link.springer.com/article/10.1186%2Fs13073-...

Lindor (2013): http://theoncologist.alphamedpress.org/content/18/...

This is an extremely complex and highly specialized area. These articles are for information only and are not a substitute for current, case-specific expert professional medical / genetic advice regarding any specific VUS in any specific gene, in the context of your personal medical and family history.

BarredOwl

[EDITED to update link to ASCO policy statement]

Agreed. The two NCCN guidelines cited above address enhanced surveillance and risk reduction strategies in the appropriate case. To complicate things further, with respect to surveillance, in certain instances, those guidelines refer one to yet a third NCCN guideline: "Guidelines for Breast Cancer Screening and Diagnosis" (Version 1.2015).

BarredOwl

My genetic counselor gave me a website to check the status of gene variants...clinvar.com (only companies that share their information will be included. Myriad, for example, does not share their information)

There is nothing new for my variant either on that website, just wanted to share it. The genetic counselor I met with (at a NCI cancer center)said that most VUS's (90% I think) end up classified as benign. Hope that is true!

Just out of curiosity, do any of you with a VUS have that VUS noted in a study or studies on clinvar? Mine has a total of 3 submissions, one by GeneDx, one by Ambry, and one by a study on women with ovarian cancer. One woman in the study had my VUS.

Thanks, Boys62! I find all of this genetic stuff very fascinating.

Thinking101, you’re in the same boat as me, only I have a VUS of BRCA 1. I’d suggest we might be waiting years to have our variations proven to be something since there are thousands of variations yet to be determined.

I have a VUS of BRCA2 and am enrolled in the PROMPT study. Here is the link if anyone is interested:

https://prompt.patientcrossroads.org/

radmom27- I too have a Variant of Unknown Significance on the BARD 1 (through Myriad). My genetic counselor did not make any recommendations based on this finding other than staying in touch. I see a breast surgeon again in a few months so that she can put together a monitoring plan. I have had 4 3D mammograms, an ultrasound, and finally an MRI since turning 40 1.5 years ago. The MRI was the only test that conclusively showed no cancer. I would be interested in hearing from others that have a VUS on BARD1 as well.