Over the past 25 years, beginning with the “breast cancer gene” (BRCA) discovery in 1995, the science of cancer genetics has been exponentially advancing. (1) More than 50 genes have been identified and associated with increasing an individual’s lifetime risk of developing cancer. As a group, these genes are believed to play a role in about 5 to 10 percent of all cancers, according to the National Cancer Institute. (2) From comprehensive medical-grade testing to do-it-yourself at-home genetic testing kits, there currently is an abundance of genetic tests to choose from. And more and more people are taking the proactive step of getting tested. “Over the next three years more than 100 million people are expected to pursue hereditary cancer testing,” says Ellen Matloff, the president and CEO of MyGeneCounsel, a company that helps people make sense of their genetic testing results. We’ve put together an up-to-date glossary of genes commonly tested for to help you keep track of what geneticists are looking at and why. Some of the genes have well-understood risk profiles. Some are less well understood and are now being researched. ATM People who inherit a variant in the ATM gene from one parent may have an increased risk of developing breast cancer, pancreatic cancer, prostate cancer, stomach cancer, bladder cancer, ovarian cancer, and lung cancer. People who inherit two abnormal copies of ATM (one from each parent) are at substantially greater risk. (4) AXIN2 Variants in the AXIN2 gene have been associated with an increased risk of colorectal cancer. (5) BARD1 This gene interacts with BRCA1 (the major gene associated with elevated breast cancer risk). Variants in BARD1 have been linked to an elevated risk of breast cancer, ovarian cancer, and neuroblastoma. (6) BMPR1A More than 60 variants in the BMPR1A gene have been found to cause juvenile polyposis syndrome, in which many noncancerous polyps develop in a person under age 20. (7) Most polyps in juvenile polyposis are benign, but it’s estimated that people with juvenile polyposis syndrome have a 10 to 50 percent risk of developing a cancer of the gastrointestinal tract, most commonly colorectal cancer. (8) BRCA1 Inherited genetic changes in the BRCA1 gene are a known cause of hereditary breast and ovarian cancer syndrome. Pathogenic variants in BRCA1 are associated with a 46 percent to 87 percent risk of breast cancer and a 39 to 63 percent risk of ovarian cancer. (9) BRCA1 has also been linked to an elevated risk of prostate cancer, pancreatic cancer, and melanoma. BRIP1 Genetic changes in the BRIP1 gene are associated with an elevated risk of breast and ovarian cancer. (10) BRIP1 has also been linked to Fanconi anemia, a condition that may cause bone marrow failure and a decrease in the production of blood cells. Fanconi anemia is also associated with an elevated risk of acute myeloid leukemia and a 10 to 30 percent increase in tumors of the head, neck, skin, gastrointestinal system, or genitals. (11) CDH1 Pathogenic variants in the CDH1 gene increase a woman’s risk of lobular breast cancer (cancer that starts in the milk-producing glands). More than 120 variants in CDH1 have been found to cause hereditary diffuse gastric cancer, and elevate the risk of stomach cancer risk to 56 to 70 percent. Inherited variants are also thought to increase risk for ovarian cancer, prostate cancer, and endometrial cancer. (12) CDK4 Variants in the CDK4 gene are associated with an increased risk of melanoma. (13) CDKN2A Inherited changes in the CDKN2A gene are associated with an elevated risk of lung cancer, melanoma, breast cancer, pancreatic cancer, and prostate cancer. According to the National Institutes of Health, while some variants in CDKN2A can lead to a single cancer, others may lead to cancer predisposition syndrome, which increases the risk of multiple types of cancer. (14) CHEK2 A CHEK2 genetic variant can almost double your risk of breast cancer. (15) Although the full scope of cancer risk associated with this gene is not yet known, research suggests it can also make you more likely to develop ovarian cancer, prostate cancer, colon cancer, kidney cancer, thyroid cancer, a brain tumor, or osteosarcoma. (16) CTNNA1 CTNNA1 genetic variants are associated with hereditary diffuse gastric cancer (HDGC). (17) DICER1 Most individuals with a pathogenic variant in the DICER1 gene rarely develop tumors; however, a variant in DICER1 may elevate the risk of cancerous and noncancerous tumors, most often in the lungs, ovaries, kidneys, and thyroid. (18) EPCAM Pathogenic variants in the EPCAM gene are associated with Lynch syndrome, a condition that increases the risk of many types of cancer, especially colorectal cancer. Six percent of all cases of Lynch syndrome are associated with genetic changes in EPCAM. (19) GREM1 Inherited variants in GREM1 are associated with polyposis syndrome mixed hereditary 1 (HMPS1), which is a condition characterized by multiple types of colorectal polyps with increased risk of colorectal cancer. (20) HOXB13 To date, at least two variants in the HOXB13 gene have been reported to raise the risk of prostate cancer. (21) KIT Genetic variation in KIT causes gastrointestinal stromal tumors, which are tumors that occur in the stomach or small intestine. Pathogenic variants in this gene are also associated with core binding factor acute myeloid leukemia. (22) MEN1 More than 1,300 variants in the MEN1 gene are associated with multiple endocrine neoplasia type 1, which often involves the development of cancerous and noncancerous tumors in the body’s endocrine (hormone-producing) glands. (23) MLH1 Inherited genetic changes in the MLH1 gene contribute to 50 percent of all cases of Lynch syndrome and increase the risk of many types of cancer. Individuals with Lynch syndrome are at an elevated risk of cancers of the colon, endometrium, ovaries, upper urinary tract, brain, stomach, and small intestine. Pathogenic variants in MLH1 have also been linked to rare skin tumors and cancers of the blood (leukemia and lymphoma). (24) MSH2 Around 40 percent of gene-mutation-related Lynch syndrome cases are caused by pathogenic variants in the MSH2 gene. Individuals with Lynch syndrome have increased risk of several types of cancer, including cancers of the colon, endometrium, ovaries, upper urinary tract, brain, stomach, gallbladder duct, and small intestine. Some variants in MSH2 are associated with rare skin tumors. (25) MSH3 Genetic variants in the MSH3 gene are associated with an increased risk of endometrial cancer and colorectal cancer. (26) MSH6 Approximately 10 percent of families with Lynch syndrome, an inherited cancer syndrome associated with a predisposition to a number of different cancers, have a pathogenic variant in the MSH6 gene. Individuals with Lynch syndrome have an increased risk of many types of cancer, including cancers of the colon, stomach, small intestine, liver, gallbladder duct, brain, and upper urinary tract. Some variants in MSH6 are also associated with rare skin tumors and an increased risk of endometrial cancer in women. (27) MUTYH If a person carries two copies of an MUTYH gene variant, he or she is considered to have autosomal recessive familial adenomatous polyposis (FAP), an inherited disorder that leads to multiple polyps in the colon and rectum that will often become malignant. If a person carries one mutated copy of the MUTYH gene, they are considered at a slightly higher risk of colon cancer than someone who does not carry the variant. (28,29) NF1 Inherited pathogenic variants in the NF1 gene increase lung cancer risk and, in rare cases, cause juvenile myelomonocytic leukemia, which is a cancer of blood-forming tissue that typically occurs in children younger than 2 years old. (31) NTHL1 Pathogenic variants in the NTHL1 gene are associated with elevated risk of colorectal cancer. (32) PALB2 Inherited variants in the PALB2 gene cause an increased risk of breast cancer, pancreatic cancer, and ovarian cancer. PDGFRA Genetic changes in the PDGFRA gene are associated with an elevated risk of gastrointestinal cancers, most commonly cancers of the stomach or small intestine. (33) PMS2 Genetic abnormalities that involve the PMS2 gene are reported in about 2 percent of families with Lynch syndrome. Lynch syndrome increases the risk of several types of cancer, including cancers of the colon, rectum, endometrium, ovaries, stomach, gallbladder duct, liver, small intestine, upper urinary tract, and brain. In some cases, there is an elevated risk of glioblastoma. Carrying two pathogenic variants in PMS2, although extremely rare, is associated with increased risk of leukemia or lymphoma. (34) POLD1 Pathogenic variants in the POLD1 gene are associated with an increased colon cancer risk as well as several other cancers. (35) POLE Genetic variation in POLE are associated with increased risk of colorectal cancer. (36) PTEN Pathogenic variants in the PTEN gene cause PTEN hamartoma tumor syndrome (PHTS), and can also contribute to Cowden syndrome, a disorder that increases the risk of cancers of the breast, thyroid, uterus, and colon. RAD50 Inherited pathogenic variants in the RAD50 gene are associated with increased risk of ovarian cancer. (37) RAD51C Pathogenic genetic variants in RAD51C are associated with increased risk of ovarian and breast cancers. (38) RAD51D Pathogenic genetic variants in RAD51D are associated with increased risk of ovarian and breast cancers. (39) SDHA Pathogenic variants in the SDHA gene are associated with an increased risk of gastrointestinal stromal tumors (GIST), which is characterized by the growth of noncancerous or cancerous tumors in the stomach or small intestine. Genetic changes in SDHA are also associated with hereditary paraganglioma-pheochromocytoma, a condition that causes noncancerous and cancerous tumors in cells near the adrenal glands, head, and neck. (40,41) SDHB The SDHB gene is involved in several cancers. It has been reported in individuals with Cowden syndrome or Cowden-like syndrome, increasing the risk of tumor growth and the risk of breast, thyroid, and endometrial cancers. Variants in SDHB are also associated with an increased risk of gastrointestinal stromal tumors (GIST), particularly stomach and kidney cancer. (42) SDHC Genetic abnormalities in the SDHC gene have been identified in a small number of individuals with gastrointestinal stromal tumors (GIST), a cancer of the gastrointestinal tract. (43) More than 30 variants in SDHA are associated with paraganglioma-pheochromocytoma, a condition that can cause noncancerous and cancerous tumors in cells near the adrenal glands, head, or neck. (41) SDHD Inherited genetic variants in SDHD cause Cowden syndrome, which is associated with an increased risk of breast and thyroid cancers as well as gastrointestinal stromal tumors (GIST), and increased risk of gastric cancers. ( 44) SMAD4 Pathogenic variants in the SMAD4 are associated with an increased risk of developing colorectal cancer. There are at least 78 variants in SMAD4 that are known to cause juvenile polyposis syndrome. (45) SMARCA4 At least six different pathogenic variants in the SMARCA4 gene have been identified in individuals with rhabdoid tumor predisposition syndrome (RTPS), which is characterized by an increased risk of developing cancerous tumors. Most often, these tumors occur in the brain, ovary, spinal cord, or in the kidney, but can also occur in other organs. (46) STK11 Genetic changes in the STK11 gene are associated with Peutz-Jeghers syndrome (PJS), a condition that causes noncancerous and cancerous tumors to form in the gastrointestinal tract. This can increase the risk of cancer in the breast, colon, pancreas, stomach, small bowel, cervix, endometrium, testicles, skin, ovary, and lung. TP53 Inherited pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome (LFS), which is associated with an increased risk of developing cancer. LFS can increase the risk of breast cancer, bone cancer, leukemia, soft tissue cancers, colorectal cancer, lung cancer, and cancer of the adrenal gland.
