Charlie was recently diagnosed with colorectal cancer. Genetic testing revealed that he had a VUS in a gene called APC. The report said his variant was in a part of the APC gene that was not predicted to lead to lots of colorectal polyps, but might still cause increased cancer risk. He was enthusiastic about connecting with family members to learn more about his variant and whether or not it was causing the cancer in his family.
Charlie first called up his sister Lori, who was 52 and also just recently diagnosed with colorectal cancer. She agreed to have the testing and was found to carry the same VUS. Charlie asked his father and mother if they would be tested at the same time, because Charlie knew that he inherited the VUS from either his mother or father. Charlie also asked his father’s brother Frank to be tested, since he knew that Frank had been diagnosed with colon cancer 15 years earlier. Charlie was surprised when his mother, Maureen, was found to carry the VUS, but his father and uncle Frank did not carry the VUS.
What about Charlie’s other brothers and sisters? They could be tested too. Siblings who carry the VUS and do not have cancer give some information about the VUS. Each sibling has a 50% chance of inheriting the VUS from their mother. Charlie asked each of his siblings if they wanted to be tested, and most of them agreed. Charlie’s siblings were the people that were easiest to contact, but more information necessary to classify this variant would need to come from distant relatives.
Once Charlie knew the variant was on his mother’s side of the family, it allowed him to focus on those relatives for the purpose of this study. Charlie knew the variant came from either mother’s mother or his mother’s father: his grandmother or his grandfather. Both of his maternal grandparents were deceased, so Charlie had to try different strategies to see which of his grandparents had his variant.
His grandmother had breast cancer at age 73. Charlie decided to try and track down a sample from her tumor. Often times, when an individual has cancer, a piece of their tumor is saved and stored. Later, it can be used to extract DNA and this can be tested. He called the hospital where his grandmother was treated 15 years earlier to see if they had any of her tumor stored. The hospital did and, with his mother’s help, Charlie was able to arrange to have some of it sent for testing.
Charlie also contacted his mother’s half-brother Eddie, who had colorectal cancer diagnosed at age 42 and also had recently been found to have 2 polyps.
Eddie also did not carry the VUS. This surprised Charlie. When the stored tumor was tested, it turned out that his grandmother Ann did not have the variant either. These results made sense together because the only way Eddie could’ve had the VUS was if Grandma Ann had it as well.
Charlie stepped back and realized that the variant would be coming from his Grandpa Kurt. Unfortunately, Grandpa Kurt had died from a heart attack years ago. There was no way to confirm that he had the VUS, but it was extremely likely that he did.
Charlie spoke with his mother, who knew about her grandfather, Dean. She also knew the first names of her aunts and uncles, but had lost contact with them years ago. She did not think any of them were still alive. With this information, Charlie decided to try to connect with his Great-Grandfather Dean’s side of the family.
Charlie started on Ancestry.com to see if he could find out any more about his great-grandfather’s family. Charlie found census and death certificate records on Great-Grandfather Dean. The death certificate said that Dean had died of throat cancer. Charlie wrote on a message board that he was looking to connect with any other descendants of his great-grandfather. A few weeks later, Charlie got a response from Johnny, the grandson of Dean, who was enthusiastic about connecting with Charlie. Johnny had been working on his family history for some time and was excited to swap family ancestry information with Charlie.
After a few emails and a long phone conversation, Charlie had learned a lot about this side of the family. Johnny, age 70, had not had cancer and had a colonoscopy that did not show any polyps, but was intrigued by Charlie’s story and was willing to be tested. Johnny was found to carry the VUS. Johnny’s mother, Elle, had passed away in her late 60’s but not from cancer. Elle must have had the VUS since she would have been the one to pass it on to Johnny.
Johnny told Charlie about his other relatives. Johnny’s aunt Cary had died young in a car accident. Johnny’s uncle Colby had died of a heart attack at the age of 92. Johnny said he could pass on contact information about Cary’s two daughters and son, and about Colby’s two living sons.
Charlie started emailing and calling Cary’s children (his first cousins once removed). Two of them were excited about meeting a new cousin but did not want to be tested. However, one of Cary’s daughters, Jill, agreed to be tested. One of Colby’s sons, Greg, was out of contact with everyone and nobody really knew where he was or what happened to him. Colby’s other son, “Uncle Finn,” was fine with sending in a saliva sample for testing. Finn mentioned that his older sister Samantha had passed away, but her daughter, Jana, who was a nurse, might be interested as well.
Johnny had never mentioned his cousin Samantha, so Charlie was surprised to find out about more descendants of his great grandfather. Jana was enthusiastic about participating and submitting a saliva sample as well. She was interested in knowing the results of the study so she could inform her children and grandchildren if they should be tested.
The results from testing for all of Charlie’s cousins came back around the same time. Jill did not have the VUS. Jana had the VUS, which meant that both her mother and her Grandfather Colby carried the VUS. Uncle Finn also carried the VUS, and while he had other health issues, he did not have any cancers. Charlie had started to notice that outside of his close family, almost everyone with the VUS did not have cancer.
Charlie was ready for some answers and connected back with the lab to piece together all the information he had found after all his hard work. You can see his final pedigree here.
Notice that you can connect all the individuals found to test positive for the VUS. It is important to note that there are people with the VUS who don’t have cancer and people without the VUS who have cancer. Charlie identified two people with the VUS and cancer, ten people with the VUS and no cancer, one person with cancer and no VUS and one without the VUS who had no cancer.
Taken as a whole this is sufficient evidence to classify this variant as benign. This meant that the APC VUS was not causing the cancer in Charlie’s family.