Information on Genetic Variants



Here are just some of the genes we are studying on PROMPT

ATM
CDH1
CHEK2
NBN
PALB2
RAD51C
RAD51D
STK11
TP53
BRCA1 & BRCA2


ATM

ATM-Related Cancer Risk

 

Medical risks associated with two defective copies of ATM

Inherited mutations in the ATM gene can cause a medical condition called Ataxia Telangiectasia (AT), a rare childhood disease that affects the nervous system, causing difficulty walking, delays in development, as well as increased risks for infection and certain cancers.  A child who is diagnosed with AT inherits two defective ATM genes, one from each parent.

Mutations in ATM have been associated with leukemia, lymphoma, and breast, stomach, bladder, pancreatic, lung, and ovarian cancers.

 What is the risk of cancer with one defective copy of ATM?

The vast majority of adults who are found to have a mutation in ATM have only one copy that is defective. The second copy of ATM gene is working and functional. There has been a great deal of debate about the significance of inheriting one defective copy of ATM with regard to cancer risk. Studies suggest that in general this results in a moderate increased risk of breast cancer (approximately 2-fold or twice that of average, which is the same degree of risk as having a first-degree relative with breast cancer). However, rare mutations in ATM may significantly elevate breast cancer risk. Recent data suggest that there may also be a risk of pancreatic cancer, but the actual risk is not yet known.

ATM cancer screening and risk-reduction options

It is not clear at this time how knowledge of an ATM mutation should change medical care. An individual’s personal and family histories are the most important factors. Based on these, female relatives in “high risk families” (multiple relatives on same side of the family affected by breast cancer) may be candidates for breast MRI screening. If there is a family history of pancreatic cancer, individuals may be eligible for clinical trials for pancreatic cancer screening.

ATM testing in other family members

At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance as testing for a high risk gene mutation does.  It is recommended that concerned family members discuss issues with their physicians.


 

For more information on ATM, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on ATM, visit our Literature page.

 


CDH1

Inherited mutations in the CDH1 gene are associated with increased risk for Hereditary Diffuse Gastric Cancer (HDGC) (an aggressive type of stomach cancer) and breast cancer. Men and women with mutations in CDH1 have up to an 80% risk for developing HDGC in their lifetime, and women have a 40-50% chance of developing lobular breast cancer in their lifetime. However, these risk percentages can vary among individuals, depending on their family history of cancer. There is emerging evidence for an increased risk for colon cancer in HDGC, but this association is still being studied.   With the uptake of gene panel testing, individuals have been identified with CDH1 mutations who do not have a family history of stomach cancer. The stomach cancer risk for individuals with the CDH1 mutation who come from such families is uncertain, but is potentially lower than the risk to those from families with a history of stomach cancer.

 CDH1 cancer screening and risk-reduction options

The identification of a mutation in the CDH1 gene could lead to major changes to medical care  including prophylactic (preventative) removal of the stomach, which is also known as a Gastrectomy.

Unfortunately, current screening tools such as endoscopy (an instrument inserted through the mouth used to visualize areas including the stomach) are not effective.  For those who carry a CDH1 gene mutation, leading experts recommend that the stomach be preventively removed regardless of any endoscopic findings.  Studies have shown that at the time of gastrectomy, most individuals with HDGC have some number of precancerous findings in their stomach that were not identified using endoscopy. Even random biopsies may miss the possible area of cancer, or pre-cancers, since there is no way to know where they are and they cannot be seen in most cases until the cancer is more advanced.

Other risk-reducing options include:

1.      Annual Endoscopy for those who decline surgery, or prior to surgery

Annual endoscopies with random biopsies should be performed to look for evidence of clinically significant lesions. All individuals need to know that it is quite possible that early gastric cancer, or pre-cancer lesions may or may not be detected in this way. These endoscopies should be performed in a medical center with special interest and expertise with HDGC.

2.      Annual Screening for Breast Cancer starting at age 35

It is recommended women undergo annual mammograms and breast MRI, and that the two screens be alternated from one another every six months. This is in addition to clinical breast exams by a physician every six months and monthly breast exams.

3.      Considering colonoscopy screening beginning at age 40, or ten years earlier than the earliest diagnosis of colon cancer in the family.

There is emerging evidence for an increased risk for colon cancer in HDGC families, but this association is still being studied. The International HDGC Consortium is recommending that this screening be initiated by age 40 and repeated every 3-5 years or sooner depending on personal history of polyps.

 CDH1 testing in other family members

Genetic testing in adult family members of those with a known CDH1 mutation should be considered.  Should an individual test positive for the CDH1 mutation, medical professionals would consider that person to be at elevated HDGC risk, in which case increased cancer surveillance would be indicated and risk-reduction options would be discussed.


 

For more information on CDH1, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on CDH1, visit our Literature page.

 


CHEK2

CHEK2-Related Cancer Risk

CHEK2 is classified as a moderate risk gene, meaning that there is a 2-4 fold increased risk of developing breast cancer.The CHEK2 gene is currently the most well-studied moderate risk gene.Individual lifetime risk assessments for individuals with CHEK2 mutations range from 20% for those with no affected family members to 44% for those with strong family history (“strong family history” is defined as more than one close relative affected with breast cancer such as a sister, mother, grandmother, or aunt). Further research is needed to understand the interactions of moderate penetrance genes and family history on lifetime cancer risk.

 The 1100delC CHEK2 Mutation

The 1100delC mutation is the most commonly identified mutation in the CHEK2 gene.  This specific mutation has been studied extensively in individuals of European ancestry.  Lifetime risks of breast cancer have been estimated at between 20-44%. As stated earlier, the risk appears higher in women who have a significant family history of breast cancer.  There also an increased risk of having a contralateral breast cancer (cancer in the other breast) for those with  prior breast cancer and the 1100delC CHEK2 gene mutation. There is currently limited information about CHEK2 gene mutations in non-European individuals.

Several studies have shown an increased risk of colon cancer in those with 1100delC CHEK2 mutation. Other cancers that have been associated in some but not all studies include prostate cancer, and melanoma, among othersThe levels of risk and cancer spectrum haven’t been fully clarified at this point in time.

Non-1100delC CHEK2 Mutations

The scientific community currently has the most information on a mutation in CHEK2 called 1100delC.  We do not yet have the same level of information for other types of CHEK2 mutations.  However, the goal is to improve the depth and scope of this knowledge over time. 

CHEK2 cancer screening and risk-reduction options

The CHEK2 gene is currently the most well-studied moderate risk gene.  However, there is currently no agreement within the medical community on the best long-term medical management for an individual who carries a mutation in the CHEK2 gene.  Healthcare providers oftentimes rely on an individual’s personal and family history to guide medical care. As research continues to evolve physicians and researchers will gain a better understanding of how a CHEK2 gene mutation will guide medical care.  Because the information provided to patients will almost certainly change, those with a CHEK2 gene mutation, or any gene mutation, are encouraged to keep in touch with their medical providers in order to receive updates.

Some options which can be considered dependent on personal and family history include increased breast surveillance such as breast MRI and colonoscopy.

CHEK2 testing in other family members

At this point in time, testing adult family members for a moderate risk gene mutation does NOT provide the same clarity or guidance as testing for a high risk gene mutation does.  It is recommended that concerned family members discuss issues with their physicians.


 

For more information on CHEK2, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on CHEK2, visit our Literature page.

 


PALB2

PALB2-related cancer risk

Inherited mutations in the PALB2 gene are associated with increased risk for breast cancer.  Because mutations in the PALB2 gene are rare (it is estimated that there is a ~0.08%, or less than 1 in 1000 chance of an individual being a PALB2 mutation carrier) and were discovered relatively recently, the cancer risks and risk estimations for this gene are still being defined. In general, the lifetime breast cancer risk by age 70 appears to range from ~35% to up to 58%, compared to the general population risk of 12%. It also appears that breast cancer risk in families with PALB2 mutations may be influenced by the number of family members with breast cancer.

PALB2 cancer screening and risk-reduction options

Women with a PALB2 mutation are encouraged to discuss the options of enhanced surveillance such as annual breast MRI, chemoprevention (taking a medication to reduce breast cancer risk), or consultation for bilateral prophylactic mastectomy (preventative removal of both breasts) based on their personal and family histories of breast cancer.

PALB2 mutations also have been detected in the setting of familial pancreatic cancer (families with one or more cases of pancreatic cancer on the same side of the family), although the lifetime risk of pancreatic cancer in PALB2 carriers has not yet been well-defined. Pancreatic cancer surveillance includes an annual endoscopic ultrasound. However, the benefits of screening are unclear and the potential harms should be carefully considered.

Furthermore, other cancers, such as ovarian cancer and male breast cancer, have been reported in PALB2 carriers, but it is unclear whether these are truly associated.

There are no known increased cancer risks in children who are carriers of a single defective copy of PALB2. Inheriting two defective PALB2 genes, one copy from the mother and one copy from the father, can cause a medical condition called Fanconi Anemia (FA), a rare newborn disease characterized by skeletal differences, bone marrow failure (cannot make enough red blood cells, white blood cells, or platelets), and risk for cancers.   This type of inheritance is called autosomal recessive and this type of FA is a very rare event.

 PALB2 testing in other family members

Genetic testing in adult family members of those with a known PALB2 mutation should be considered.  Should an individual test positive for the PALB2  mutation, medical professionals would consider that person to be at elevated risk, in which case increased cancer surveillance would be indicated and risk-reduction options would be discussed.

Given the lack of consensus data surrounding PALB2, a challenging question is whether an individual who tests negative for a known familial PALB2 mutation has residual hereditary cancer risk, possibly due to other genes. These issues need to be considered in the context of the family history.


 

For more information on PALB2, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on PALB2, visit our Literature page.

 


RAD51C

RAD51C-related cancer risk

RAD51C is a member of the RAD51 family.  Mutations in RAD51C has been shown to be associated with an increased risk of ovarian cancer. Studies are underway to better estimate the lifetime risk of ovarian cancer. Studies are conflicting as to whether there is an increased risk of   breast cancer with RAD51C mutations.

There are no known increased cancer risks in children who are carriers of a single defective copy of RAD51C.  Inheriting two defective RAD51C genes, one copy from the mother and one copy from the father, can cause a medical condition called Fanconi Anemia (FA), a rare newborn disease characterized by skeletal differences, bone marrow failure (cannot make enough red blood cells, white blood cells, or platelets), and risk for cancers.   This type of inheritance is called autosomal recessive and this type of FA is a very rare event.

RAD51C cancer screening and risk-reduction options

There are currently no guidelines for medical management for an individual who carries a mutation in the RAD51C gene.  Healthcare providers oftentimes defer to an individual’s personal and family history to guide medical care. As research continues to evolve physicians and researchers will gain a better understanding of how a RAD51C gene mutation will guide medical care.  Because the information provided to patients will almost certainly change, those with a RAD51C gene mutation, or any gene mutation, are encouraged to keep in touch with their medical providers in order to receive updates.

Some options which can be considered dependent on personal and family history include ovarian cancer screening and oophorectomy.

RAD51C testing in other family members

At this point in time, testing family members for a moderate risk gene mutation does not provide the same clarity or guidance as testing for a high risk gene mutation does.  It is recommended that concerned family members discuss issues with their physicians.


 

For more information on RAD51C, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on RAD51C, visit our Literature page.

 


RAD51D

RAD51D-Related Cancer Risk

 

RAD51D is a member of the RAD51 family. RAD51D is involved in the Fanconi Anemia (FA) –BRCA pathway, which is critical for DNA repair. Mutations in the RAD51D gene present an increased susceptibility for breast and ovarian cancer. Relative cancer risk is estimated at 1.32 times the general population for breast cancer and 6.3 times the general population for ovarian cancer. This translates to nearly a 10% lifetime risk for ovarian cancer.

RAD51D cancer screening and risk-reduction options

There are currently no guidelines for medical management for an individual who carries a mutation in the RAD51D gene.  Healthcare providers oftentimes defer to an individual’s personal and family history to guide medical care. As research continues to evolve physicians and researchers will gain a better understanding of how a RAD51D gene mutation will guide medical care.  Because the information provided to patients will almost certainly change, those with a RAD51D gene mutation, or any gene mutation, are encouraged to keep in touch with their medical providers in order to receive updates.

Some options which can be considered dependent on personal and family history include ovarian cancer screening and oophorectomy.

RAD51D testing in other family members

At this point in time, testing family members for a moderate risk gene mutation does NOT provide the same clarity or guidance as testing for a high risk gene mutation does.  It is recommended that concerned family members discuss issues with their physicians.


 

For more information on RAD51D, visit the Genetics Home Reference.

For scientific publications on RAD51D, visit our Literature page.

 


STK11

STK11-related cancer risk

Mutations in the STK11 gene are associated with Peutz-Jegher Syndrome (PJS), also known as hamartomatous intestinal polyposis. PJS occurs when hamartomatous polyps (benign) are found either in the small intestine, colon or stomach, and can form blockage which leads to abdominal pain, bleeding, and anemia. Individuals with PJS have up to an 80% lifetime risk of cancer, and the most predominant cancers are breast cancer and colon cancer.  The lifetime risk for a woman with PJS of developing breast cancer is approximately 50% and the lifetime risk of developing colon is approximately 39%.  Polyps may arise in the colon in individuals as young as 8 years old. Other cancer risks include pancreas (36%), stomach (29%), small bowel (13%), ovarian (21%), uterine (9%), testes, and lung (15%).

Recommendations for family members

Genetic testing in children and adult family members of those with a known STK11 mutation should be considered.  Should an individual test positive for the STK11 mutation, medical professionals would consider that person to be at elevated risk, in which case increased cancer surveillance would be indicated and risk-reduction options would be discussed.


 

For more information on STK11, visit the Genetics Home Reference and the National Cancer Institute.

For scientific publications on STK11, visit our Literature page.

 


TP53