Genes involved in Hereditary Cancer Syndromes - How to use this list
Who should see a Cancer Genetics Specialist?
Sydney Cancer Genetics is a private, specialised medical service supporting individuals and families concerned about cancer.
We provide genetic counselling and genetic testing (including BRCA1 and BRCA2) throughout Australia
Our staff includes Genetic Oncologist Dr Hilda High. Dr High sees patients throughout Australia via Telehealth and face to face in Sydney from rooms in Wahroonga and Ultimo.
For a list of both public hospital based familial cancer clinics and other private cancer genetics services see The Human Genetics Society of Australasia.
APC
In the classic form, 100 to 1000s of polyps develop in the colon. The polyps start appearing in the early teens and left untreated these polyps almost always become cancerous. The classical form is associated with a phenotype that includes desmoids, cysts in the jaw (osteomas), harmless changes in the eye (CHRPE) and polyps elsewhere in the gastrointestinal tract.
There is also a milder, attenuated form with 10s to 100s of polyps, usually appearing at a later age.
This syndrome has also been called Gardner syndrome in the past.
There is a 50% chance of a person who carries an APC mutation, whether male or female, passing the mutation to their son or daughter. If a mutation is identified, then predictive testing would be available for blood relatives, including children in this case.
There’s lots that can be done to reduce risk. For more information, see the links below
The Centre for Genetic Education fact sheet on Hereditary Bowel Cancer.
The US National Library of Medicine’s Genetics Home Reference page on Familial Adenomatous Polyposis
You may also find the Cancer Institutes FAP brochure useful, although the eviQ page provides the most up to date screening and testing advice.
The Cancer Institute’s eviQ pages provide accurate management and testing guidelines. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
We haven’t found a specific Australian Support Group for this syndrome yet. If you know of one, please tell us!
ATM
If an individual inherits one copy of the ATM gene with a mutation, the lifetime risk of breast cancer increases. With one a specific ATM (c.7271T>G) mutation, the lifetime risk of breast cancer is high (similar to that associated with a germline BRCA2 gene mutation.)
If an individual inherits mutations in the ATM gene from both their mother and their father (autosomal recessive) Ataxia-Telangiectasia syndrome occurs. This is rare condition, affecting 1 in 40,000 to 100,000 people worldwide. It causes severe disability and is usually diagnosed in early childhood. It is characterised by poor co-ordination and balance (“ataxia”) and small clusters of enlarged blood vessels that are red or purple and often spidery in appearance and are seen in the eyes and on the skin (“telangiectasia”). The immune system may also be weakened.
There’s lots that can be done to reduce risk. For more information, see the links below
- The US Genetics Home Reference site has information on the condition, how it is inherited as well as management advice.
- The Cancer Institute’s eviQ pages provide accurate management and testing guidelines for women who carry the ATM (c.7271T>G) mutation. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
- BrAsh AT is a support group for individuals and families affected by Ataxia-Telangiectasia. It is based in Queensland but runs activities throughout Australia.
BAP1
Inherited (germline) BAP1 mutations are associated with benign melanocytic naevi (“moles”) occurring at an early age. BAP1 mutations also cause an increased risk of melanoma at an older age, especially of the skin but also of the eye (uveal melanoma). Mesothelioma (a cancer of the lining of the chest cavity, usually associated with asbestos exposure) is more common.
BAP1 related cancer syndrome is very rare and scientists are still learning about the lifetime cancer risks.
There’s lots that can be done to reduce melanoma risk. The most important is to avoid excess sun exposure. High risk families or people who have already had a melanoma should have annual skin checks with their doctor.
For more information, see the links below
- Most articles on BAP1 are “scholarly” and no link to a patient friendly site is available, to our knowledge, at this time.
- Melanoma support groups:
– The Melanoma Institute Australia
– Melanoma Patients Australia - There are many support groups for people with mesothelioma, although most relate to absestos exposure.
– The Australian Mesothelioma Society has a list.
BARD1
BMPR1A
BRCA1 or BRCA2
These genes are stable. You are very unlikely to be the first person in your family to develop a germline (heritable) mutation, although you may be the first person to get a BRCA related cancer.
Founder mutations (that is, mistakes in a particular spot in the gene’s code) are known to occur when groups of people are separated due to religious, ethnic or geographic reasons over long periods of time. This was the case for the Ashkenazi Jewish people who moved into central and Eastern Europe almost 2 thousand years ago. That’s why women who have breast or ovarian cancer are asked about Jewish heritage: it is nothing to do with the religion itself! A woman of Ashkenazi heritage who has breast or ovarian cancer is significantly more likely to carry a BRCA mutation and is eligible publicly funded testing.
Triple negative breast cancer (that is ER negative, PR negative and HER2 negative) has a strong association with BRCA mutations. For women diagnosed with triple negative cancer at or before age 50, the likelihood she carries a BRCA mutation ~10%. In Australia, publicly funded genetic testing is therefore available for these women, regardless of family history. Women diagnosed with triple negative at an older age may elect to have BRCA testing, especially if they have a family history of BRCA-related cancers.
Although originally named because of the increased risk of breast cancer, BRCA mutations also increase the risk of ovarian cancer. There is a >10% chance that a woman who is diagnosed with a high grade serous ovarian cancer before age 70 carries a BRCA mutation. In Australia, publicly funded genetic testing is therefore available for these women, regardless of their family history.
Recent research suggests that in men whose prostate cancer has spread to their other organs or bones that they have up to a 10% chance of carry a BRCA mutation. This could be higher if there is a family history of BRCA-related cancers.
There is a lot that can be done to reduce cancer risk.
Some women, like Angelina Jolie, elect to have bilateral mammograms. This is the most effective way to reduce breast cancer risk. For women who don’t have mastectomies, annual breast screening with mammograms should start at age 30. Annual breast MRI is included between the ages of 30 and 50.
There is no effective screening for ovarian cancer at the moment. The blood tests and ultrasounds are just not sensitive enough to detect the cancer before it has had a chance to spread to the surrounding tissues. Instead, the ovaries and tubes should be removed by age 40 for a BRCA1 mutation carrier and age 45 for a BRCA2 mutation carrier.
There is a 50% chance of a person who carries a BRCA1 or BRCA2 mutation, whether male or female, passing the mutation to their son or daughter. If a mutation is identified, then predictive testing would be available for adult blood relatives.
There’s lots that can be done to reduce risk. For more information, see the links below
- The Centre for Genetic Education fact sheet on Hereditary Breast and Ovarian Cancer.
- The US National Library of Medicine’s Genetics Home Reference page on BRCA1 and BRCA1
- The Cancer Institute’s eviQ pages provide accurate management and testing guidelines. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
There are many support groups in Australia. Your local hospital probably has one. These are just a few national groups:
BRIP1
CDH1
CDKN2A and CDK4
In Australia, melanoma is the 3rd most common cancer. It affects 1:18 people, mainly over age 60.
When 2 or more first degree relatives (close relatives such as your parents, brothers and sisters or children) have had a melanoma, it is referred to a familial malignant melanoma syndrome.
Increased risk of melanoma can be caused by genes that affect how someone looks (their “phenotype”) and how their skin reacts to sun exposure. These features include fair or red hair; pale skin; blue or green eyes, naevi (“moles”).
In some families, the risk is also increased because of a mutation in a particularly gene, such as CDKN2A (other genes included CDK4, BAP1, POT1, ACD, TERF2IP and TERT). These kind of inherited gene mutations are rare. For example, the average Australian diagnosed with a melanoma has only a 2% chance that it was caused by an inherited CDKN2A mutation. However, for someone has had 3 or more melanomas and also has 2 or more close family members who have had a melanoma, the chance may be as high as 60%.
There’s lots that can be done to reduce melanoma risk. The most important is to avoid excess sun exposure. High risk families or people who have already had a melanoma should have annual skin checks with their doctor. These checks should include dermoscopy, total-body photography and/or sequential digital dermoscopy imaging.
For more information, see the links below
- Melanoma support groups:
– The Melanoma Institute Australia
– Melanoma Patients Australia
CHEK2
FLCN
Mutations in the Folliculin gene (FLCN) are associated with Birt Hogg Dubé syndrome (BHD). It is very rare, with around 400 families known worldwide.
Individuals with BHD almost always develop small skin coloured lumps on the face and chest (benign skin tumours called fibrofolliculoma) which appear in the 20s. Individuals with BHD have a high chance of developing cysts in the lungs and the kidneys. Kidney tumours occur in 20 to 30% of individuals. These tend to be bilateral, multifocal and slow growing. In some cases these tumours may develop into cancers.
Because of the risk of pneumothorax, a medicalert bracelet should be worn and smoking and high ambient pressures should be avoided.
Screening for renal tumours should start at age 20 with an abdominal MRI, followed by annual high quality renal ultrasound.
The severity of the signs and symptoms vary among affected individuals, even within families, and is not predictable.
There is a 50% chance of a person who carries an FLCN mutation, whether male or female, passing the mutation to their son or daughter. If a mutation were identified, then predictive testing would be available for adult blood relatives. However, as current genetic testing does not identify a mutation in all individuals who meets the clinical diagnosis of Birt Hogg Dubé syndrome, their first degree relatives (parents, siblings and children) should have at least baseline screening from age 20.
There’s lots that can be done to reduce risk. For more information, see the links below
- The US Genetics Home Reference site has information on the condition, how it is inherited as well as management advice.
- The Cancer Institute’s eviQ pages provide accurate management and testing guidelines for individuals with Birt Hogg Dubé syndrome. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
- BHD Foundation is a support group for individuals and families affected by Birt Hogg Dubé syndrome. It is based in the USA but has members worldwide.
We haven’t found a specific Australian Support Group for this syndrome yet. If you know of one, please tell us! - Rare Cancers Australia is a support group for individuals and families affected by rare cancers.
GREM1
MEN1
MET
MLH1, MSH2, MSH6, PMS2 or EPCAM
MUTYH
NBN
NF1
PALB2
POLD1
POLE
PTCH
PTEN
RAD51C; RAD51D
RET
SDHB, SDHD, SDHC, SDHA, SDHAF2
A mutation in one of the SDH family of genes (SHDA, SDHB, SDHC, SDHD and SDHAF2) is associated with the Hereditary Paraganglioma Pheochromocytoma syndrome.
It is characterised by the development of paraganglioma and/or pheochromocytoma (“pheos” for short). In some cases, stomach cancers (called GISTs or GastroIntestinal Stromal Tumours) and/or kidney cancers occur. The likelihood of these tumours and cancers developing depends on which of the SDH genes is affected.
The Hereditary Paraganglioma Pheochromocytoma syndrome is very rare, affecting 1 in a million people.
Paraganglioma and pheos can be associated with mutation in other genes including
- the VHL gene (associated with Von Hippel Lindau syndrome)
- the RET gene (associated with Multiple Neuroendocrine syndrome)
- the NF1 gene (associated with Neurofibromatosis type 1)
Paraganglioma and pheos are very rare tumours. However, when they occur, there is a 10% to 30% chance that they occurred because of a germline (inheritable) gene mutation. Genetic testing is nearly always recommended. Often the clinical or family history and/or staining tests of the tumour gives a clue as to which gene may be involved. If not, a pheo gene panel test to check the 10 or more pheo genes may be recommended.
Paraganglioma arise from tissue that is part of the nervous system and that runs along the outside of the spine. This tissue is called the sympathetic and parasympathetic nervous system. Pheos are tumours found in the adrenal gland above the kidney. The tumours may grow and press on other structures. Sometimes they may become cancerous and spread.
Pheos and paraganglioma that arise in the sympathetic nervous system usually secrete hormones, especially if located in the chest, abdomen or pelvis. These hormones are involved in the “flight or fight response”. They are called catecholamines and include hormones such as adrenalin. The symptoms of intermittent catecholamine excess include episodes of heart palpitations associated with high blood pressure, facial flushing, headaches and sweating.
There is a 50% chance of a person who carries a germline SDH mutation, whether male or female, passing the mutation to their son or daughter. If a mutation were identified, then predictive testing would be available for adult blood relatives. This allows screening of at risk relatives to start early. The SDHD gene is unusual: the mutation almost never causes problems if it is inherited from the mother (this is called imprinting).
There is lot’s that can be done to reduce risk. Individuals with an SDHB, SDHC or SDHD gene mutation should start screening from ages 5 to 10, depending on the mutation type. (The SDHA gene mutations are less likely to cause problems). This allows early detection and treatment of tumours. Screening includes annual blood pressure measurements and fasting blood tests as well as imaging of the spine, kidneys and adrenals every 2 to 3 years.
The SDH genes are involved in pathways that are switched on when oxygen levels are low. People with SDH and other paraganglioma and pheo gene mutations should not smoke or live at high altitudes.
For more information, see the links below:
- Genetics Home Reference site has information on Hereditary Paraganglioma Pheochromocytoma syndrome associated with the SDH family of genes
- The Cancer Institute’s eviQ pages provide accurate management and testing guidelines for individuals with a mutation in the SDH family of genes. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
- The Pheo Para Trooperssupport group is for individuals and families with a mutation in the SDH family of genes or affected by Paraganglioma and/or Pheochromocytoma. They are based in the USA but have members around the world.
SMAD4
STK11
Mutation in the STK11 gene are associated with Peutz-Jeghers syndrome. It is a rare cancer syndrome, affecting 1 in 25,000 to 1 in 300,000 people.
Individuals with Peutz-Jeghers syndrome develop hamartomatous polyps. These are non cancerous growths that occur mainly in the small intestines, large intestines and the stomach. These polyps may first occur in childhood. They can cause bleeding and, as they can grow large, can cause abdominal pain and recurrent bowel obstructions and/or intussusception
Individuals with Peutz-Jeghers syndrome usually develop freckling (actually dark blue to dark brown macules) on the lips and inside the mouth as well as around the mouth, lips and nostrils. While freckles are very common, it is very unusual to have many on the lips or inside the mouth. These dark macules appear in childhood but may fade as a person gets older.
Peutz-Jeghers syndrome is associated with an increased risk of cancer of the large and small intestine, stomach, pancreas, breast and ovary. Women may develop a very rare form of cervical cancer (that is not associated with the HPV virus) and men can develop a rare tumour of the testes called large calcifying Sertoli cell tumours, which secrete oestrogen.
There is a 50% chance of a person who carries a STK11 mutation, whether male or female, passing the mutation to their son or daughter. If a mutation were identified, then predictive testing would be available for adult blood relatives.
There’s lots that can be done to reduce risk. Screening for gastrointestinal tumours should start at age 10 and for women, breast screening should start at age 30.
For more information, see the links below
- The US Genetics Home Reference site has information on the condition, how it is inherited as well as management advice.
- The Cancer Institute’s eviQ pages provide accurate management and testing guidelines for individuals with STK11 mutations. The site is open to patients and doctors: they just ask that you register so that can track usage. Go to www.eviQ.org.au and look under Cancer Genetics, Management in the left hand Category Menu
- The Peutz-Jeghers Syndrome Online Support Group is a support group for individuals and families affected by Peutz-Jeghers syndrome. It is based in the USA but has members worldwide.