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.


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

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 ( 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.

Resources and more reading on VUS:

American Society of Human Genetics on VUS

Mayo Clinic pdf on VUS

Think Genetic LFS VUS

Rethinking PINK in October- Why Andi Doesn’t Do Pink and What YOU CAN DO To support Breast Cancer Awareness.

Andi Last is a breast cancer survivor. She has LFS and explains why she does not do PINK in October. She also gives us some valuable facts on breast cancer and many ways to TAKE ACTION to help Breast Cancer Patients, Raise Awareness and Actually support Breast Cancer Research. 


Andi doesn’t do Pink.

October is National Breast Cancer Awareness Month. “Pinktober.” This disease isn’t pink or fun, it’s deadly. If you update your Facebook status for a day or post a silly photo to “raise awareness,” don’t forget to back it up with real action: donate blood, platelets, bone marrow or hair. Donate money to worthy organizations. If you’re of appropriate age, get a mammogram. Links and info below.

“The party atmosphere often surrounding pink ribbon promotions and campaigns conceals the harsh, devastating effects of breast cancer. We are not celebrating a holiday. This is not a sporting event where the side wearing the most team colors wins.” – from DivineMrsM, a forum member with Stage IV incurable breast cancer

Breast cancer awareness isn’t about “saving second base.” Here’s the reality:

– Over 40,000 people will die of breast cancer in the US in 2016.

-There will be over 246,000 new cases of invasive breast cancer in the US this year. About 2,600 of them will be men.

-Metastatic breast cancer (spread of the cancer, usually to the brain, liver, lungs or bones) is incurable. Metastatic disease is the initial diagnosis for about 5% of all new U.S. breast cancer cases each year.

-Nearly 3 in 10 women who have had early breast cancer will eventually develop metastatic disease.

-Up to 10% of female breast cancer cases are on account of genetic mutations. BRCA1, BRCA2, p53, CHEK2, ATM and -PALB2 gene mutations have all been linked to breast cancer.

(Stats provided by The American Cancer Society, Breast Cancer Facts & Figures 2015-2016.)

Ultimately, if you have cancer, statistics mean nothing. Reality is either 100% or 0%.


You can specify that you want it to go to research, and you can check organizations at before deciding where to donate. I personally recommend the following organizations:

  • LivingLFS – My breast cancer in 2015 was due to Li-Fraumeni Syndrome (LFS), an inherited genetic disorder that makes me prone to all sorts of cancers. LivingLFS encourages, empowers, and educates those living with Li-Fraumeni Syndrome by connecting them with care, resources, and others who are Living LFS.
  • FORCE – Facing Our Risk of Cancer Empowered – Improving the lives of individuals and families affected by hereditary breast, ovarian, and related cancers.
  • – the site where I learned most everything when I was initially diagnosed.

While 30% of all breast cancer patients will metastasize (that is, have their cancer spread to other areas), only about 2% of funding goes to investigate metastatic breast cancer.

These sites support metastatic breast cancer patients:


  • If you’re 40 or over, check the guidelines and schedule a mammogram if appropriate.
  • If you have a family history of cancer, consider genetic testing. If you’re diagnosed with cancer and have a genetic mutation, it may affect your treatment choices.