Amelia was recently diagnosed with breast cancer. Genetic testing found that she had a VUS in a gene called BRCA1. Amelia wanted to see if she could find out more about how her variant travels in her family. Amelia was excited to start exploring both her mom and dad’s side of the family to find which side of her family the variant came from. Because she has two copies of each gene, one from mom, and one from dad, first she has to figure out if the VUS is from her mom or dad in order to narrow down her search.
Amelia decided to start by asking her mom, dad, and sisters to send saliva samples to be tested. She knew that the variant could come from either side of her family. She wanted her sisters to be tested as well, since they were about her age and each had a 50% chance of carrying the variant. She suspected the variant might come from her mom’s side of the family, because her mom had breast cancer at age 70, but it would be good to sure. See the beginning of Amelia’s pedigree.
After being tested Amelia’s mom was tested and found to carry the variant. Because of this, her mom’s brother and sister (Amelia’s aunt and uncle) also had a 50% chance at carrying the variant. Amelia knew her aunt and uncle well, and it was not hard for her to contact them and ask if they were willing to be tested to see if either of them had her VUS. Her uncle Mike was tested and found to carry the variant, and so was his daughter Emma, who had breast cancer diagnosed at age 50. However, Aunt Betty did not have the variant.
The hard part was going to be finding other relatives from her mom’s side of the family since Amelia did not know her cousins very well. She called her Grandma Irene, (her mom’s mom). She knew that her Grandma Irene stayed in touch with everyone.
Grandma Irene told Amelia that her mother, Amelia’s great grandmother Jean, died of some type of cancer at age 74. Grandma Irene was not sure where it started. Later that day Amelia found death records using a public website and found out that Great grandmother Jean actually died of skin cancer.
Grandma Irene also told Amelia about her sisters and brother. None of them had cancer, but two of them already died. Grandma knew all seven of her nieces and nephews, and even knew that one of her nieces had been diagnosed with breast cancer in her 60s.
So, where should Amelia look next? Because her mom and her mom’s brother had the variant, she knew the variant had to come from one of their parents. She asked Grandma Irene and Grandpa Jim to send saliva samples to see which of them had it. It turned out that Grandpa Jim had the variant. This was surprising because Amelia was expecting the variant to be in her Grandmother Irene, since there was cancer on that side of the family. She realized that she did not need to contact Grandma Irene’s niece who had cancer, that niece would not have inherited the VUS from her Grandpa Jim. That is why testing is so valuable, because you can potentially show which cancers in a family are connected genetically, and which are not.
Amelia’s search had narrowed to Grandfather Jim’s genetic relatives. Grandpa Jim did not remember anything about his family, but Grandma Irene knew that Jim’s sister Joan died a long time ago at age 40, and thought it was cancer. Amelia had to ask her mother, who thought that Aunt Joan had died of ovarian cancer. Sometimes, when people die from cancer, a piece of their tumor is saved and stored, and they call this a “tumor block”. Later, DNA can be extracted from the tumor and tested. Unfortunately, nobody knew where to find tumor block for Joan, so Amelia needed to find another relative.
Amelia’s mother did not have any contact with Grandpa Jim’s family, but knew several of their names. Amelia went to Facebook and started looking for anyone she could find on that side of her family. Soon Amelia was able to connect with her second cousin, Maya, who was also in her 40’s.
Maya was eager to talk to Amelia because Maya had recently been diagnosed with breast cancer. They talked about the VUS project and Maya was not only willing to be tested, but wanted to help connect Amelia with her side of the family and see who else might be tested. Maya was considering genetic testing for her breast cancer and was worried about her daughter’s cancer risk. Maya confirmed that her grandmother, Joan, had ovarian cancer. No one else in Maya’s immediate family had cancer.
Maya noted that several of her aunts and cousins also had breast cancer. Amelia knew that some of them might have her variant and others might not, so Maya and Amelia decided to work together to get as many of Maya’s relatives tested as they could. Maya contacted her two brothers, Rob and Chris. Maya also told her sister, Em, about the study, but Em declined testing.
With Maya’s help, Amelia was able to contact 8 additional relatives who agreed to be tested. They were: Joan’s brother, Craig; his daughters, Lisa and Holly, who both survived breast cancer; Craig’s third daughter, Kate, who had not had cancer; and Holly’s daughter Tiffany, who was also recently diagnosed with breast cancer.
Amelia really felt like she was starting to get somewhere!
The testing from Maya’s relative came back at the same time. Maya was found to carry the VUS. Amelia was excited to find this out because it meant that Maya’s mom Suzie and her grandmother Joan also had the VUS. Rob had the VUS. Chris didn’t. Craig, had the VUS. Lisa and Holly, Craig’s daughters, had the variant. Kate, who did not have cancer, also did not have the VUS. Tiffany had the VUS.
With the laboratory’s help, Amelia was able to piece together all the information she found. Notice that you can connect all the individuals found to test positive for the VUS with her Grandpa Jim’s parents. It is important to notice that there are people with the VUS who don’t have cancer, and people without the VUS who do have cancer. Amelia identified 7 women with the VUS and cancer 2 women with the VUS and no cancer, one woman with cancer but not the VUS, and 6 women without the VUS who had no cancer.
Taken as a whole this is sufficient evidence to classify this variant as likely pathogenic. With this evidence Amelia’s family members will be able to have their test results confirmed in a clinical laboratory. Amelia’s family members can have appropriate follow up screening.
Amelia’s, Tiffany’s, Maya’s, Lisa’s, and Rob’s children are all at risk of inheriting the VUS. The adult children that are found to have the variant may want to be tested immediately. Most children at risk are teenagers and too young to develop breast cancer. Most genetic counselors would consider teenagers to young to be tested. They could be tested when they are older. If they carry the variant they could take actions to prevent breast and ovarian cancer.