What is hereditary cancer?

Cancer development is a complex process. If certain genes are mutated and do not give cells proper instructions about when to grow and divide, then cancer could develop. 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-associated 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.

Some types of cancer have a significant hereditary component and can develop due to a mutation in one of the hereditary cancer predisposition genes. Most breast cancer occurs by chance however about 10% is inherited. Mutations in certain genes are known to be significantly associated with increased risk of breast and/or ovarian cancers and other types of cancer. About 50% of all hereditary breast cancer cases can be attributed to BRCA1/2 mutations and about 30% of the cases are associated with known mutations in other genes, such as ATM, CDH1, PALB2, PTEN, TP53 and others.

Are you at high risk for breast or ovarian cancer?

You could have an inherited risk if:

  • You or a family member (mother’s or father’s side) were diagnosed with breast cancer at age 50 or younger
  • Breast and ovarian cancer in the same woman in your family
  • Male breast cancer at any age
  • 3 or more cases of breast cancer on the same side of the family
  • 3 or more cases of breast, ovarian and/or pancreatic cancer on the same side of the family
  • Ashkenazi (Eastern European) Jewish ethnic background and a personal or family history of Hereditary Breast and Ovarian Cancer Syndrome

What is BreastDx ClearTM?

BreastDx ClearTM is an expanded multi-gene test that analyses point mutations, gross deletions and duplications in the following genes associated with inherited breast, ovarian and some other types of cancer: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD51C, RAD51 D, STK11 and TP53. We use next-generation sequencing (NGS) technology to identify variants in the coding regions of these genes. The identified variants are classified according to the guidelines for sequence variant interpretation of the American College of Medical Genetics and Genomics (ACMG). 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.

What are the possible benefits of BreastDx Clear testing?

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 guide your medical care and decrease the risk of breast and ovarian cancers.


BreastDx ClearTM genes

BreastDx ClearTM is a multi-gene test that analyzes 16 breast cancer susceptibility genes. Although all women have some risk of developing breast and/or ovarian cancer at some point in their lives, having a mutation in one of the breast cancer susceptibility genes increases this risk. Men who have a mutation in one of the breast cancer susceptibility genes have an increased risk of breast, prostate, pancreatic, gastric and other cancer types.


GENE LIST
APC ATM BRCA1 BRCA2 BRIP1 CDH1 CHEK2 FANCC MRE11A NBN PALB2 PTEN RAD51C RAD51D STK11 TP53
Click on any gene to view its definition

APC - This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene.

ATM - The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

BRCA1 - This gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA1 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA1 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA1 protein plays a critical role in maintaining the stability of a cell's genetic information.

Research suggests that the BRCA1 protein also regulates the activity of other genes and plays an essential role in embryonic development. To carry out these functions, the BRCA1 protein interacts with many other proteins, including other tumor suppressors and proteins that regulate cell division.

BRCA2 - This gene provides instructions for making a protein that acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

The BRCA2 protein is involved in repairing damaged DNA. In the nucleus of many types of normal cells, the BRCA2 protein interacts with several other proteins to mend breaks in DNA. These breaks can be caused by natural and medical radiation or other environmental exposures, and they also occur when chromosomes exchange genetic material in preparation for cell division. By helping to repair DNA, the BRCA2 protein plays a critical role in maintaining the stability of a cell's genetic information.

Researchers suspect that the BRCA2 protein has additional functions within cells. For example, the protein may help regulate cytokinesis, which is the step in cell division when the fluid surrounding the nucleus (the cytoplasm) divides to form two separate cells. Researchers are investigating the protein's other potential activities.

BRIP1 - The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations

CDH1 - This gene provides instructions for making a protein called epithelial cadherin or E-cadherin. This protein is found within the membrane that surrounds epithelial cells, which are the cells that line the surfaces and cavities of the body. E-cadherin belongs to a family of proteins called cadherins whose function is to help neighboring cells stick to one another (cell adhesion) to form organized tissues.

E-cadherin is one of the best-understood cadherin proteins. In addition to its role in cell adhesion, E-cadherin is involved in transmitting chemical signals within cells, controlling cell maturation and movement, and regulating the activity of certain genes. E-cadherin also acts as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way.

CHEK2 - The CHEK2 gene provides instructions for making a protein called checkpoint kinase 2 (CHK2). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way.

The CHK2 protein is activated when DNA becomes damaged or when DNA strands break. DNA can be damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material.

In response to DNA damage, the CHK2 protein interacts with several other proteins, including tumor protein 53 (which is produced from the TP53 gene). These proteins halt cell division and determine whether a cell will repair the damage or self-destruct in a controlled manner (undergo apoptosis). This process keeps cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors.

FANCC - This gene provides instructions for making a protein that is involved in a cell process known as the Fanconi anemia (FA) pathway. The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is blocked due to DNA damage. The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs). ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked together, which stops the process of DNA replication. ICLs can be caused by a buildup of toxic substances produced in the body or by treatment with certain cancer therapy drugs.

The FANCC protein is one of a group of proteins known as the FA core complex. The FA core complex is composed of eight FA proteins (including FANCC) and two proteins called Fanconi anemia-associated proteins (FAAPs). This complex activates two proteins, called FANCD2 and FANCI, by attaching a single molecule called ubiquitin to each of them (a process called monoubiquitination). The activation of these two proteins, which attach (bind) together to form the ID protein complex, attract DNA repair proteins to the area of DNA damage so the error can be corrected and DNA replication can continue.

MRE11A - This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

NBN - This gene provides instructions for making a protein called nibrin. This protein is involved in several critical cellular functions, including the repair of damaged DNA.

Nibrin interacts with two other proteins, produced from the MRE11A and RAD50 genes, as part of a larger protein complex. Nibrin regulates the activity of this complex by carrying the MRE11A and RAD50 proteins into the cell's nucleus and guiding them to sites of DNA damage. The proteins work together to mend broken strands of DNA. DNA can be damaged by agents such as toxic chemicals or radiation, and breaks in DNA strands also occur naturally when chromosomes exchange genetic material in preparation for cell division. Repairing DNA prevents cells from accumulating genetic damage that may cause them to die or to divide uncontrollably.

The MRE11A/RAD50/NBN complex interacts with the protein produced from the ATM gene, which plays an essential role in recognizing broken strands of DNA and coordinating their repair. The MRE11A/RAD50/NBN complex helps maintain the stability of a cell's genetic information through its roles in repairing damaged DNA and regulating cell division. Because these functions are critical for preventing the formation of cancerous tumors, nibrin is described as a tumor suppressor.

PALB2 - This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2.

PTEN - This gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of three oxygen atoms and one phosphorus atom. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell growth that can lead to the formation of tumors.

RAD51C - This gene is a member of the RAD51 family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 and are known to be involved in the homologous recombination and repair of DNA. This protein can interact with other RAD51 paralogs and is reported to be important for Holliday junction resolution. Mutations in this gene are associated with Fanconi anemia-like syndrome. This gene is one of four localized to a region of chromosome 17q23 where amplification occurs frequently in breast tumors. Overexpression of the four genes during amplification has been observed and suggests a possible role in tumor progression. Alternative splicing results in multiple transcript variants.

RAD51D - The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene.

STK11 - This gene (also called LKB1) provides instructions for making an enzyme called serine/threonine kinase 11. This enzyme is a tumor suppressor, which means that it helps keep cells from growing and dividing too fast or in an uncontrolled way. This enzyme helps certain types of cells correctly orient themselves within tissues (polarization) and assists in determining the amount of energy a cell uses. This kinase also promotes a type of programmed cell death known as apoptosis. In addition to its role as a tumor suppressor, serine/threonine kinase 11 function appears to be required for normal development before birth.

TP53 - This gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way.

The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.

Because p53 is essential for regulating cell division and preventing tumor formation, it has been nicknamed the "guardian of the genome."