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


Li-Fraumeni in the movies

by Andi Last  –  Sean Hannity and Hercules have made Travis Tritt the first person to ever say the words “Li-Fraumeni Syndrome” in a major motion picture.

Back in 2014, LFS was used in a plot line on the TV show, Grey’s Anatomy. Ann Ramer recapped the episode here. For a condition as rare as ours, this was a big deal in the LFS community.

On October 27, 2017, Let There Be Light was released in movie theaters across the country, bringing LFS to the general public once again. (Thank you Susan Frary for letting us know!)

Fox’s Sean Hannity is executive producer of this faith-based film that stars Kevin Sorbo (Hercules, Andromeda) in his directorial debut, and real-life wife Sam Sorbo. Sam Sorbo also co-wrote the film with Dan Gordon, screenwriter on movies like Passenger 57 and TV shows like Highway To Heaven. SPOILER ALERT: If you haven’t seen the film and are wanting to, you may want stop here, there are some details mentioned below about the plot.

Let There Be Light movie posterDr. Sol Harkens (Kevin Sorbo) is a celebrity author and the world’s most famous atheist as a result of the death of his 8 year old son, Davey, from a brain tumor. That genetics could be involved is teased early in the film in Harkens’ debate with a Christian cleric. Harkens says, “I’m willing to say my son’s death was just plain bad luck, a quirk of genetics, a bad roll of the cosmic dice, or maybe some corporate villain who poisoned the water.” He says if he were a praying man, he’d pray to see his son one more time, but that would mean praying to the very so-called God that killed him.

Harkens is estranged from his Christian wife, Katie (Sam Sorbo) and their remaining two sons (played by the couple’s real-life sons). With his life spiraling out of control, Harkens drives drunk, has a car accident, and is clinically dead for 4 minutes. In that time he indeed sees Davey again. Davey tells his father it isn’t his time, and “Let There Be Light.” Harkens returns to consciousness a changed man. The world’s biggest atheist finds God. The Harkens make plans to remarry – and to fulfill Davey’s request by creating a LTBL phone app to send light across the world to Heaven on Christmas Eve, with Sean Hannity as their media partner. The family seems to be back on their way to happily ever after as Christmas nears – until tragedy strikes again.

Katie has a seizure just like Davey’s. In the hospital the next morning, a doctor (played by country star Travis Tritt) comes to talk to the couple. He says, “We’ve had a chance to study the MRI and the CT scan, and we’ve gotten a pretty detailed look at your blood work.” Sol asks for the doctor’s specialty. Upon learning that the doctor is an oncologist, the Harkens understandably freak out. Katie cries, “It was me, wasn’t it? I gave it to him, didn’t I, Doctor? I gave our son cancer.” The oncologist tells her no. He says, “the blood work indicates that you have Li-Fraumeni Syndrome. People with Li-Fraumeni Syndrome are susceptible to various types of cancer, including brain tumors.” They discuss her prognosis and options, then the family goes on to make the most of the time they have left together.

In one scene, Katie tells her boys that whatever happens to her is God’s will, that she doesn’t believe in death, that it’s like she’ll just be in the next room. Katie dies in Sol’s arms on Christmas Eve as the world shines their LTBL lights to heaven and her family sings “Silent Night.”

Of course, Let There Be Light isn’t at all intended to be a primer on Li-Fraumeni Syndrome. Like with the episode of Grey’s Anatomy, there were inaccuracies due to time constraints. That LFS is inherited is implied when Katie dramatically asks if she gave her son cancer, but that the oncologist vehemently tells her no confuses the fact that LFS is indeed inherited at least 80% of the time. Genetic testing was never mentioned. Genetic test results aren’t available for next-day delivery – at least not yet. Maybe some day. Mentioning that the other two sons have a 50/50 chance of also having LFS and asking about family history would’ve been a responsible way to educate about the condition, perhaps even prompting audience members to wonder about their own family history, do more research and consider genetic testing themselves. But the goal of this movie is simply to encourage faith in difficult times. Opening a whole can of realism worms that prevent the story from wrapping up with a bittersweet Christmas Eve bow wouldn’t help.

Li-Fraumeni Syndrome was simply  the tragic vehicle chosen to convey Let There Be Light‘s message of hope. Katie’s tragedy could’ve been completely unrelated to her son’s, and the story would’ve still held together. It makes me wonder if there is a true LFS story in the lives of one of the screenwriters. If so, it’s a story I would like to hear. In the meantime, I hope that Let There Be Light might turn on a light of recognition and awareness next time those movie goers hear mention of Li-Fraumeni Syndrome.

UPDATE: The day after this blog post was released, I received a message from Dan Gordon, the co-screenwriter and producer for Let There Be Light, and we now have our answer: Dan’s brother had LFS. Dan was kind enough to grant me an interview for the Learning Li-Fraumeni Syndrome podcast. I’m so grateful to Dan Gordon for sharing his very personal story, and helping us bring awareness to LFS!

Read more real stories of hope from real Li-Fraumeni Syndrome families on this blog, and on our Facebook page.

#LetThereBeLight #ShareTheLight