Variants of Unknown Significance on Genetic Tests

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Angtee15
Angtee15 Member Posts: 209

Hello! I ended up getting an inconclusive result on my Breast Next test. I have a variant of unknown significance on the PTEN gene. I know it's not an uncommon result but I am curious if anyone out there had these variants later classified as mutations? Also did this factor into your treatment plan? I've already settled on a bmx before my results and I can't help but feel this genetic "ambiguity" supports this decision.

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  • Anonymous
    Anonymous Member Posts: 1,376
    edited February 2016

    On your Ambry report there should be somewhere that says "Polyphen" or "SIFT" results. If it says "benign" or "tolerated" that means the variance has been shown to be benign in a lab. If it says "malignant" or "not tolerated" that means it's likely to cause breast cancer. Your choice to do a Bmx is completely up to you. I had a variance in the BARD1, which says "benign" in the Polyphen and SIFT. I didn't know about my results until after surgery, but I had decided on a mastectomy anyway so it wouldn't have changed my choice.

  • SummerAngel
    SummerAngel Member Posts: 1,006
    edited February 2016

    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).

  • barbe1958
    barbe1958 Member Posts: 19,757
    edited February 2016

    I had an VUS on my BRCA2 gene a number of years ago. I wonder if they've come up with more information on it....how would I find out? I had it done after my initial surgery as my daughter and sister wanted to know.

  • Angtee15
    Angtee15 Member Posts: 209
    edited February 2016

    Hi ladies! I checked my Ambry report and it says "this alteration is predicted to be probably damaging and deleterious by Polyphen and SIFT in silico analyses." I need to circle back with the genetic counselor because she made it sound like this was probably nothing while this sounds like it's not the case. Hmmm. Color me confused.

    Thanks for your input! I am going with the BMX regardless but I will make sure I understand my report. I hope you are well!

  • kleigh1
    kleigh1 Member Posts: 1
    edited March 2016

    I've received results from genetic testing that say I have a "variant of unknown significance" for BRCA2. I'm getting annual MRI screenings now for my breasts, and so far, so good. I'm more worried about the increased risk for ovarian cancer, which feels even scarier to me. I'm 40, and my gynecologist says that we shouldn't consider removing my ovaries until I'm 45. Instead, she's recommended I go on microgestin (the birth control pill) to "suppress" my ovaries and decrease the chances for any abnormal growth. Has anyone heard of this has a strategy? Also, aren't there conflicting reports about microgestin increasing breast cancer risk? Do I have to choose between protecting my ovaries and protecting my breasts? I appreciate any info you have.

  • Moderators
    Moderators Member Posts: 25,912
    edited March 2016

    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:

    Survey on Genetic Testing

    https://www.surveymonkey.com/r/testinggenetics

    If you've been diagnosed with breast cancer or have a family history of the disease, you may have considered or undergone genetic testing to learn if you have a BRCA1, BRCA2, or other genetic mutation linked to a higher risk of breast cancer.

    We'd like to understand more about you and your thought processes as you made the decision to have or not have genetic testing.

    Thank you for completing the survey. We will compile the results and share them with the community!

    Also, please private message us with any feedback or questions you have regarding our survey!

    The Mods

  • Hopeful82014
    Hopeful82014 Member Posts: 3,480
    edited March 2016

    Barbe, you could contact the genetic counselor who initiated your earlier testing, if available, for an update. Otherwise, I'd try contacting the testing lab.

    My testing was done through Myriad and showed one deleterious PALB2 mutation and another gene with a VUS. Unfortunately, unlike Ambry, they don't list the Polyphen or SIFT results, either.

  • barbe1958
    barbe1958 Member Posts: 19,757
    edited March 2016

    I might do that hopeful....

  • ShetlandPony
    ShetlandPony Member Posts: 4,924
    edited March 2016

    Kleigh1, if I were you I would get an opinion from a cancer genetics expert, and ask that doctor, your oncologist (or whoever is monitoring you with breast MRIs), and your gynecologist to consult together about your particular case. Or you could go to a big cancer center where all these specialists are already gathered, for a second opinion. I had BRCA testing a few years ago. At that time the cancer genetics doctor gave me a paper with National Comprehensive Cancer Network guidelines. It shows for BRCA2 a 20% lifetime risk of ovarian cancer, which is termed high risk. For this group it says, "Removal of ovaries and fallopian tubes, upon completion of childbearing, ideally by age 35 to 40 or, otherwise: Transvaginal ulatrsound & CA-125 blood test every 6 mo." I don't know if this applies to your mutation, or if there have been any changes to the guidelines. But I would not rely just on the gynecologist's opinion.

    Barbe, I agree with Hopeful. The lab that did your genetic testing can probably run your results through their system to check for updates. I think it is called re-curating.

  • BarredOwl
    BarredOwl Member Posts: 2,433
    edited March 2016

    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

  • ShetlandPony
    ShetlandPony Member Posts: 4,924
    edited March 2016

    Yes, thank you, BarredOwl for emphasizing the importance of genetic counseling, and of asking the expert whether any guidelines even apply to your case.

  • Traveltext
    Traveltext Member Posts: 2,089
    edited March 2016

    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". 


  • barbe1958
    barbe1958 Member Posts: 19,757
    edited March 2016

    I agree with Traveltext, the experts had nothing significant to say about my VUS. Except to watch for melanoma....but they said that was due to the breast cancer in the first place.

  • BarredOwl
    BarredOwl Member Posts: 2,433
    edited January 2017

    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]

  • ShetlandPony
    ShetlandPony Member Posts: 4,924
    edited March 2016

    And an expert opinion on clinical management can can include recommendations about appropriate surveillance.

  • BarredOwl
    BarredOwl Member Posts: 2,433
    edited March 2016

    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

  • Metta
    Metta Member Posts: 84
    edited March 2016

    I had a VUS on the ATM gene, and GeneDx said DO NOT base any medical decisions on that. My genetic counselor and doctor agreed that I should not consider the variant when deciding what type of surgery to have. As it turned out, I had to have a mastectomy on one side and decided to just have a prophylactic mastectomy at the same time. I'm not sure what the right decision was, but I didn't want to deal with years of anxiety, MRIs, etc.

    I registered in in the Prompt study, which helps researchers gather more information about variants: https://promptinfo.squarespace.com


  • Rambros
    Rambros Member Posts: 78
    edited March 2016

    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)

  • barbe1958
    barbe1958 Member Posts: 19,757
    edited March 2016

    Boys2 I tried to get info off that link, but as we are patients with UNknown varianats, it's hard to check to see what no one knows! LOL

  • Rambros
    Rambros Member Posts: 78
    edited March 2016

    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!

  • Traveltext
    Traveltext Member Posts: 2,089
    edited March 2016

    Agree with barbe1958, that's such a confusing site. When I feel like checking on the latest status of my BRCA1 VUS, I just Google it. Nothing has shown up to date!



  • SummerAngel
    SummerAngel Member Posts: 1,006
    edited March 2016

    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.

  • Rambros
    Rambros Member Posts: 78
    edited March 2016

    my VUS only has 1 submission, by Ambry in 2014. No studies listed

  • SummerAngel
    SummerAngel Member Posts: 1,006
    edited March 2016

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

  • DandelionHair
    DandelionHair Member Posts: 15
    edited March 2018

    I have a VUS BRCA 2.


    I was told to not worry, it was an unknown variant. I'm in Chemo treatment for stage 2, invasive Breast Cancer
    My younger sister has the same variant with no cancer except skin.
    Relatives have a history of Cancer and all have had skin cancer
    I hope to follow this thread to learn more about the variant of unknown significance gene.

    Thank you
  • Traveltext
    Traveltext Member Posts: 2,089
    edited March 2018

    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.


  • besa
    besa Member Posts: 1,088
    edited March 2018

    http://www.lerner.ccf.org/gmi/research/pten.php

    This is not an answer to you question but possibly a way to at least put a PTEN VUS on the table to be studied and further research on this topic. A genetic counselor would be needed to help become part of this Cleveland Clinic study. Just a possible option if you are interested....

  • JuniperCat
    JuniperCat Member Posts: 658
    edited March 2018

    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
    radmom27 Member Posts: 6
    edited May 2018

    I just found out I have VUS of BARD 1. My counselor was very vague and just said they do not have any information on this mutation, only I can't be positive or negative. I was tested by Genpath.

    Anyone else with BARD 1?

  • sacchetti7
    sacchetti7 Member Posts: 1
    edited May 2018

    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.

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