What is hereditary cancer?

There are many genes that control cell growth and division. If certain genes are mutated and do not give cells proper instructions about when to grow and divide, then cancer could develop. Cancer development is a complex process. Environmental factors, such as UV light, tobacco and diet can increase mutation rates. Some of these mutations will be repaired, but some mutations will not. These mutations will be present in some cells in the body and this will increase the risk of cancer development. However in families with hereditary forms of cancer, a mutation is present in a very important gene and is present in all cells in the body. Inheriting a cancer-causing mutation in one of the cancer susceptibility genes does not mean that cancer will definitely occur. It means only that your risk is higher than for someone who does not carry such a mutation in their cells.

Lynch Syndrome, also called Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome, is caused by a mutation in one of five Lynch syndrome-predisposing genes: EPCAM, MLH1, MSH2, MSH6, and PMS2. Lynch syndrome accounts for 2-4% of all colorectal cancer cases and 2-5% of all endometrial cancer cases. In the United States 1 person in 400 is a carrier of one of the Lynch syndrome predisposing pathogenic variants that can increase the risk of developing colorectal, endometrial, gastric, ovarian, hepatobilial, intestinal, brain, pancreatic, prostate and skin cancer.

Who should consider genetic testing for Lynch Syndrome?

You could have an inherited risk if:

  • You have a personal or family (mother’s or father’s side) history of early onset colorectal or endometrial cancer (<50 yrs)
  • History of two or more associated cancers
  • 3 or more relatives on the same side of the family with the same type of associated cancers
  • Abnormal Microsatellite Instability (MSI) and Immunohistochemistry (IHC) tumor test results


What are the possible benefits of genetic testing for Lynch syndrome?

Any hereditary cancer susceptibility testing reduces the uncertainty about the risks of cancer for people and their families. Such testing may be able to explain the cancer history in your family. If a cancer predisposing mutation is identified, it can help your doctor to provide more personalized surgical and ongoing surveillance plans and informed treatment decisions.


What is LynchDx ClearTM?

LynchDx Clear is a next-generation assay that analyzes point mutations, gross deletions and duplications in the following five genes associated with Lynch Syndrome: EPCAM (only gross deletions and duplications are tested), MLH1, MSH2, MSH6, and PMS2. Identified variants are classified according to the guidelines for sequence variant interpretation of the American College of Medical Genetics and Genomics (ACMG).5-6 Variant classification categories include pathogenic, likely pathogenic, variant of unknown significance (VUS), likely benign, and benign with likely benign and benign variants excluded from the report.

  • Pathogenic variants - Genetic changes with known clinical significance that is associated with an increased risk of hereditary cancer.
  • Likely pathogenic variants – Genetic changes that have some preliminary clinical data indicating an association with hereditary cancer but not sufficient to make a definitive determination of pathogenicity.
  • Variants of uncertain significance (VUS) – Genetic changes with either conflicting or no supporting data to determine their pathogenicity.
  • Negative Result – No variant of clinical or uncertain significance was detected. Negative result does not eliminate the risk of developing cancer. Benign variants that have sufficient evidence to be considered of no clinical significance and likely benign variants that are not likely to increase the risk of cancer will not be shown on the report.

LynchDx ClearTM genes tested

GENE LIST
EPCAM MLH1 MSH2 MSH6 PMS2
Click on any gene to view its definition

EPCAM This gene provides instructions for making a protein known as epithelial cellular adhesion molecule (EpCAM). This protein is found in epithelial cells, which are the cells that line the surfaces and cavities of the body. The EpCAM protein is found spanning the membrane that surrounds epithelial cells, where it helps cells stick to one another (cell adhesion). In addition, the protein in the cell membrane can be cut at a specific location, releasing a piece called the intracellular domain (EpICD), which helps relay signals from outside the cell to the nucleus of the cell. EpICD travels to the nucleus and associates with other proteins, forming a group (complex) that regulates the activity of several genes that are involved in cell growth and division (proliferation), maturation (differentiation), and movement (migration), all of which are important processes for the proper development of cells and tissues.

MLH1 This gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MLH1 protein joins with another protein called PMS2 (produced from the PMS2 gene), to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. The repairs are made by removing a section of DNA that contains mistakes and replacing the section with a corrected DNA sequence. The MLH1 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

MSH2 This gene provides instructions for making a protein that plays an essential role in DNA repair. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH2 protein joins with one of two other proteins, MSH6 or MSH3 (each produced from a different gene), to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

MSH6 This gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where mistakes have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

PMS2 This gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. The PMS2 protein joins with another protein called MLH1 (produced from the MLH1 gene) to form a protein complex. This complex coordinates the activities of other proteins that repair mistakes made during DNA replication. Repairs are made by removing the section of DNA that contains mistakes and replacing it with a corrected DNA sequence. The PMS2 gene is a member of a set of genes known as the mismatch repair (MMR) genes.