Variants of Uncertain Significance(VUS) in LFS

Few things are more frustrating than looking for answers and getting the response- we don’t know. Sometimes, a person agonizes over the decision to be tested for a hereditary cancer syndrome like LFS, finally getting tested just to know for sure. Unfortunately the results aren’t always a clear cut; Yes, you have LFS or No, you do not have LFS.

There are thousands and thousands of changes that can occur to our DNA, called mutations. Not all mutations are harmful- whether or not the mutations are “bad” is a personal opinion. There are mutations that we just don’t know if they are harmful or harmless, in the case of LFS, we don’t know if the mutation is associated with cancer.  They are called Variants of Uncertain Significance (VUS),  also known as Variants of Unknown Significance (still VUS), or  Unclassified Variants.

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Li-Fraumeni Syndrome is associated with mutations in the TP53 gene. TP53 makes a tumor suppressor, so if the tumor suppressor doesn’t work right, we sprout tumors. There are many spots on the DNA, where mutations can occur. Some change the way the gene works, some do not. Sometimes the gene only works a little bit.  For more reading on mutations and how they affect us, you can read our blog “Some MUTATIONS are NONSENSE“.

When classifying variants (changes in DNA/mutations) there is a scale from 1-5 – Benign to Pathogenic. Benign (B9 to experienced mutants) means not harmful or more importantly not malignant. Pathogenic means to cause a disease- in our case, cancers.

  1. Benign means there is no change caused by the variant.
  2. Likely Benign means suspected to not cause disease.
  3. Uncertain are VUS (Variants of Uncertain Significance) this means there is not enough data to know if the mutation will cause disease or not.
  4. Likely Pathogenic means the variant is suspected to cause disease.
  5. Pathogenic means the variant is known to cause disease.

 

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Genomic Variant Scale from ASHG.org

The American Society of Human Genetics (ASHG) advises that VUS should not be used for decision making, they are neither good nor bad, and all medical decisions should be based on medical findings and family history. This does not mean you are negative for a mutation, it simply means there is a mutation there and that we do not have enough information to momentarily identify what the risk is. The best bet is to consult with a trusted geneticist or genetic counselor (www.nsgc.org) to evaluate your risk based on what you do know – your medical history, your family history, and other relevant factors.

Things to Remember:

You cannot interpret what is not known. Li-Fraumeni Syndrome is rare, we just don’t have the research numbers to know if VUS are linked to cancers. Not everyone with LFS linked mutations get cancer. We know some mutations are linked to certain cancers in LFS but there is still a lot of uncertainty. Participating in studies, such as PROMPT help record data and could help predict if certain VUS might be linked to risk of certain cancers or not.

Focus on what you can control. You can control diet, exercise, and other contributing factors to a healthy lifestyle. Although we can not control mutations, we can try to reduce our risk. A genetic counselor can help you evaluate risk and decide what and if a screening regimen would be good for you. Many people with LFS follow the Toronto Protocol, however, the best regimen is the one that works best for you, your risk, insurance coverage, and lifestyle.

As we learn more, classifications can change. When TP53 was first discovered, it was thought to be an oncogene, a gene that causes cancer. After decades of research, it was reclassified as a tumor suppressor gene. Keeping up with current research can help you advocate for yourself and live LFS.

LLFS Board Member Andi connected with Wendy Kohlmann, MS, CGC, a licensed genetic counselor at the University of Utah Huntsman Cancer Institute. In this excerpt from her interview for the Learning Li-Fraumeni Syndrome podcast, she explains what it means when your genetic test results show a VUS: a variant of uncertain significance or variant of unknown significance.

Like our page to see more segments from Learning Li-Fraumeni Syndrome, a new video and audio podcast presented by Living LFS: https://www.facebook.com/LivingLFS/

Resources and more reading on VUS:

American Society of Human Genetics on VUS

Mayo Clinic pdf on VUS

Think Genetic LFS VUS


World Rare Disease Day 2016: Li-Fraumeni Syndrome

World Rare Disease Day is February 29, 2016. Living LFS is teaming up with Global Genes to raise awareness about Li-Fraumeni Syndrome and Rare Diseases.

LLFS 2016 Rare Aware

GlobalGenes.org is a patient advocacy organization for rare diseases. Their mission is to eliminate the challenges of rare disease by building awareness, educate the global community and provide critical connections and resources that equip advocates like Living LFS to become advocates for their disease.  Their mission is so similar to ours for the Li-Fraumeni Syndrome community. Living LFS joined the Global Genes RARE Foundation Alliance in 2015 because although we have a small patient population, according to the Global Genes website, “collectively the rare disease community is larger than the AIDS and Cancer communities combined.”  Even though the actual diseases are unique, many of the issues we face with rare conditions are similar and by sharing experiences and resources we can help each other navigate for a better quality of life.

Round LLFS Hope

80% of Rare Diseases are Caused by Faulty Genes.

LFS is one of those Diseases, caused by mutations in the TP53 Tumor Suppressor Gene. People with LFS are at risk for many different cancers over their lifetime and many times multiple cancers. Although LFS mutants have higher risk of cancer, advances in early detection and new screening methods help us live longer, healthier lives.

LLFS heart rare

Show your love for someone RARE.

Approximately 50% of People Affected by Rare Diseases are CHILDREN.

Approximately 50% of LFS cancers happen before the age of 30. Half of the LFS core cancers are RARE childhood cancers such as choroid plexus tumors or adrenocortical carcinomas.  Soft tissue Sarcomas and Osteosarcomas are seen often in kids with TP53 mutations. Because of such a strong link between sarcomas and TP53 mutations, Dana Farber Cancer Institute began recommending all children who present with sarcomas be referred for genetic counseling.

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Make your own profile badge at globalgenes.org.

In the US, a disease is Considered RARE if it affects fewer than 200,000 people. 

Some literature says 400-500 families worldwide are affected with LFS. Others say that many families exist in the US alone. We don’t know how many are actually affected with LFS because not all people with LFS get cancer. We do know it is rare and that many physicians do not know a lot about it. This makes getting good care for our community extra difficult.

 

How Can You HELP?

-Help others be AWARE.

Share information about Li-Fraumeni Syndrome with friends, family, or care providers. This year we are wearing our Living LFS shirts and Jeans and making it a goal to talk to at least one person about Li-Fraumeni Syndrome.  Not sure what to say? Just talk from your heart and your experience living LFS.  You can refer them here to our website at livingLFS.org or download our informational pdf and print it out to share.

LFS-Card_ONLINE

 

-Share You’re RARE.

I AMLLFS

You can share your story here in a blog post. It helps others to know they are not alone in living LFS. Feel free to post at our public Facebook page and let us know how you are living LFS.  Wear your living LFS shirt and take the opportunity to tell people who ask- What’s LFS?  that you are living with a hereditary cancer syndrome.

Contact US to SHARE your story.

-Show You CARE.

I <3 Someone Living LFS

Let your friends or family who are rare know how much you care. Send them a message or a text just to say hi. Update your profile picture to one of the great badges supplied by globalgenes.org or create one of your own that tells someone who is facing a rare disease that you support them.

We are Rare. We Care.