The majority of cancer is not hereditary. Most cancers are random, or sporadic, and caused by risk factors, which may include the natural aging process, environmental factors, lifestyle factors (such as smoking), and random events. In fact, only 5% to 10% of cancer is hereditary.

Hereditary cancer risk can be passed from generation to generation in a family, like other hereditary traits, such as height and eye color. These types of hereditary traits are passed from parent to child through genes, which are like instructions written in a code—called DNA. While some genes determine traits like eye color or height, others help to protect the body from developing cancer. If a harmful change (known as a pathogenic variant or mutation) is present in a gene that is important in protecting against cancer, then the pathogenic variant stops the gene from working properly, resulting in an increased risk for that person to develop cancer over their lifetime. This is known as having a hereditary cancer syndrome.

There are over 50 known hereditary cancer syndromes, some of which are better-known, such as Hereditary Breast and Ovarian Cancer (HBOC) syndrome and Lynch syndrome, and others that are lesser-known, including familial adenomatous polyposis (FAP) syndrome and von Hippel-Lindau (VHL) syndrome. Regardless, each hereditary cancer syndrome is caused by pathogenic variants in different genes, and the risk for cancer in each syndrome varies.

For instance, pathogenic variants in the BRCA1 and BRCA2 genes that are associated with HBOC syndrome cause an increased risk for cancer of the breast, ovaries/fallopian tubes, prostate, and pancreas, whereas pathogenic variants in the APC gene that are associated with FAP syndrome increase the risk of developing multiple colon polyps, as well as the risk for cancer in the colon and rectum, small intestine, stomach, pancreas, thyroid, brain, and liver.

People with a hereditary cancer syndrome may develop cancer at younger ages and have a higher risk of developing more than one cancer. In families with a hereditary cancer syndrome, it is common for relatives to be diagnosed with the same or related types of cancer. This is because relatives have shared DNA and, in families with a hereditary cancer syndrome, these relatives have inherited the same pathogenic variant that puts them at risk for cancer.

Genetic testing can help to determine if a person has a hereditary cancer syndrome. It is typically recommended for people with a personal or family history of early-onset cancer (i.e., a cancer diagnosed at or younger than age 50), more than one cancer in the same person, the same cancer in two or more close relatives, an unusual presentation of cancer (such as men with breast cancer), or for people from certain ancestral backgrounds, including those with Ashkenazi Jewish ancestry.

The results of genetic testing can help a health care provider evaluate a person’s risk for certain types of cancer and recommend increased cancer screening or other steps they can take to minimize the risk of developing cancer.

“Identifying hereditary cancer syndromes has been revolutionary for cancer care and screening,” says Veda Giri, MD, division chief of Clinical Cancer Genetics and director of the Cancer Genetics & Prevention Program. “Genetic testing is now informing how best to treat cancers with targeted therapies and to determine surgical management for specific cancers. Furthermore, cancer screening can be tailored based on genetically informed risk to include an earlier age to begin cancer screening and potentially adding in advanced screening approaches. By using these approaches, we can empower patients and families to be proactive with their health and support their cancer treatment and screening needs.”

People inherit two copies of each gene, one from each of their parents. Hereditary cancer syndromes are typically inherited in an autosomal dominant or autosomal recessive pattern:

• Autosomal dominant. Many hereditary cancer syndromes are autosomal dominant. In this type of inheritance, inheriting a single pathogenic variant from either parent causes the hereditary cancer syndrome. In this form of inheritance, the parents, children, and siblings of a person with a hereditary cancer syndrome each have a 50% chance of having the same pathogenic variant. Both males and females are at equal risk of inheriting and passing on the pathogenic variant.
  
  In rare cases, an individual with an autosomal dominant hereditary cancer syndrome is found to have a pathogenic variant, but it was not inherited from a parent. Instead, the pathogenic variant is new and occurred randomly in that person when they were conceived. This is called a ‘de novo’ pathogenic variant. In these rare cases, parents would not be at risk of having the same pathogenic variant, so it is unlikely that siblings could share the same pathogenic variant. Each child of a person with a de novo pathogenic variant would have a 50% chance of having the same pathogenic variant.
• Autosomal recessive. Some hereditary cancer syndromes are autosomal recessive. In this type of inheritance, a person inherits two pathogenic variants—with one pathogenic variant inherited from each parent—resulting in a hereditary cancer syndrome. If both parents have a pathogenic variant, there is a 25% chance a child will inherit both copies of the pathogenic variant from each parent and have a hereditary cancer syndrome.
  
  Parents of an individual with an autosomal recessive hereditary cancer syndrome who have one pathogenic variant are known as carriers. In some cases, carriers may also have an increased risk of developing cancer. Siblings of an individual with this type of hereditary cancer syndrome have a 25% chance of having the hereditary cancer syndrome (both pathogenic variants were inherited), a 50% chance to be a carrier (meaning only one pathogenic variant was inherited), and a 25% chance of not having the hereditary cancer syndrome and also not being a carrier (meaning none of the pathogenic variants were inherited). Children of an individual with this type of hereditary cancer syndrome will be carriers of at least one pathogenic variant. Their risk of having the same hereditary cancer syndrome depends on whether their other parent also has a single pathogenic variant in the same gene.

Not all cancers that occur in multiple members of a family are caused by a hereditary cancer syndrome. In some cases, multiple people in a family may develop the same type of cancer because they share the same risk factors, such as smoking cigarettes or exposure to a toxic chemical.

However, the risk factors below suggest that someone may have a hereditary cancer syndrome:

• Having cancer at a younger age (age 50 or younger) than is typically seen in the average population
• Developing more than one cancer in:
  • the same part of the body (for instance, two colon cancers)
  • different parts of the body (for instance, breast and ovarian cancer)
  • sets of paired organs (for instance, cancer develops in both breasts, eyes, or kidneys)
• A type of cancer occurs in a person whose sex is uncommonly affected (for instance, breast cancer in males)
• Two or more first-degree relatives (parents, siblings, or children) who develop the same type of cancer, a rare type of cancer, and/or cancers known to occur in a given hereditary cancer syndrome
• Same or related types of cancers occurring in more than one generation of a family

Genetic testing looks for genes associated with hereditary cancer syndromes and may be recommended if a hereditary cancer syndrome is suspected based on someone’s personal and/or family history, or if someone has a family member with a known hereditary cancer syndrome.

Genetic testing is most often completed from a blood or saliva sample, which is then used to examine the DNA code of the genes related to a hereditary cancer risk. This testing typically looks at several genes at once and is often called “panel genetic testing.”

It’s important to note that some genes on a panel may not have been studied for as long or as well as others, or there may be more limited information about the cancer risks and recommended screening and prevention strategies for people with pathogenic variants in certain genes.

There are three types of genetic test results a person can receive:

• Positive: A positive result means a pathogenic variant was found in a hereditary cancer gene that increases the risk of developing certain cancers or tumors. Typically, gene-specific cancer screening or risk-reduction options are available for those individuals who test positive. Family members are also at risk of having the same pathogenic variant and may wish to consider their own genetic counseling and testing.
• Negative: A negative result means no pathogenic variants were found in any of the genes related to hereditary cancer. Cancer screening and risk-reducing recommendations are then based on someone’s personal and family history of cancer. Depending on family cancer history, other relatives may still benefit from their own genetic counseling and testing.
• Inconclusive (variant of uncertain significance, VUS): A variant of uncertain significance (VUS) result means a change, or variation, was found, but it is not known if this change is a pathogenic variant (associated with an increased risk of certain cancers) or a benign variant (not associated with an increased risk of cancer). Most laboratories will contact the ordering provider if they are able to reclassify the variant in the future. Most variants are later reclassified as benign (or normal gene changes). Cancer screening and risk-reducing recommendations are typically based on someone’s personal and family history of cancer. Genetic testing for the VUS in family members without a personal history of cancer is not typically recommended. However, based on the family history of cancer, genetic counseling may be recommended for other family members.

People who receive a positive result should talk to a genetic counselor or other health care provider with expertise in hereditary cancer syndromes to learn more about cancer screening recommendations, ways to reduce their risk of getting cancer, and the possible impact on cancer treatment. Those who receive a positive result should also inform their family members about the pathogenic variant, as they may be at risk of having the same pathogenic variant.

Over 50 hereditary cancer syndromes have been identified. Examples include:

• Hereditary Breast and Ovarian Cancer (HBOC) syndrome. HBOC is caused by pathogenic variants in the BRCA1 and BRCA2 genes. Females with HBOC have an increased risk of developing cancer of the breast, ovaries, fallopian tubes, and peritoneum. Males with HBOC have an increased risk for prostate and breast cancer. Both males and females with HBOC have an increased risk of developing pancreatic cancer and melanoma.
• Lynch syndrome. Lynch syndrome is caused by pathogenic variants in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes. Males and females with Lynch syndrome have an increased risk of developing colorectal, stomach, small intestine, pancreatic, urinary tract, brain, and some types of skin cancer. Females have a higher risk of developing uterine and ovarian cancer; males may have a higher risk of developing prostate cancer. Lynch syndrome may also be referred to as Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome.
• Familial adenomatous polyposis (FAP) syndrome. FAP, a type of gastrointestinal polyposis syndrome, is caused by pathogenic variants in the APC gene. Males and females with FAP have an increased risk of developing multiple (often 100s to 1,000s) colon polyps, resulting in an increased risk of developing colorectal cancer. People with FAP can also develop polyps in the stomach, resulting in an increased risk of stomach cancer. The cancer risk in people with FAP is also increased for the small intestine, pancreas, thyroid, liver, brain, and adrenal glands. They may also develop tumors of the soft tissue, known as desmoid tumors.
• Li-Fraumeni syndrome (LFS). Li-Fraumeni syndrome is caused by pathogenic variants in the TP53 gene. Males and females with Li-Fraumeni syndrome have an increased risk of developing multiple different types of cancers. The cancers most seen in people with LFS include female breast cancer, sarcomas of the bone or soft tissue, brain tumors, and cancer of the adrenal glands. These cancers often can develop in children. People with LFS also have a higher risk of developing more than one cancer when compared to other hereditary cancer syndromes.
• Peutz-Jeghers syndrome (PJS). PJS is caused by pathogenic variants in the STK11 gene (also known as the LKB1 gene). Males and females with PJS have an increased risk for cancer in the colon and rectum, stomach, small intestine, pancreas, and lungs. Females have an increased risk of developing breast, uterine, ovarian, and cervical cancer. Males have an increased risk of developing testicular cancer.

When a person is found to have a pathogenic variant causing a hereditary cancer syndrome, they have a greater than average risk of developing certain types of cancer. However, not everyone who has a hereditary cancer syndrome will develop cancer.

“The Cancer Genetics & Prevention Program at Yale/Smilow offers cutting-edge genetic testing for patients and their families, integrating standard-of-care genetic testing and research opportunities,” says Dr. Giri. “We deliver care through multiple avenues to ensure every patient who needs genetic testing can have access with informed decision-making for genetic testing. Our program offers the gold standard of genetic counseling, a new Fast-Track approach for expedited genetic testing, and point-of-care testing. We partner closely with clinical teams across the health system to meet the needs of patients, families, and health care providers to reduce the burden of cancer and promote health through genetically informed personalized care.”