On this page
Hereditary breast cancer (moderate-penetrance genes)
Also known as Hereditary breast cancer (CHEK2) · Hereditary breast cancer (ATM)
This condition involves an inherited change in specific genes, such as ATM or CHEK2, which can lead to an increased lifetime risk of developing breast cancer. It affects individuals who inherit these genetic changes, and understanding this risk can guide personalised screening and management strategies.
Available at Jeen Health
Clinical tests that include this
Overview
Hereditary breast cancer associated with moderate-penetrance genes refers to an inherited tendency to develop breast cancer due to specific genetic changes. Unlike high-penetrance genes (e.g., BRCA1/2) that confer a substantial risk, moderate-penetrance genes, such as ATM and CHEK2, are linked to a more modest, but still increased, lifetime risk of breast cancer [PMID:33658210]. This means that while an individual with such a genetic change has a higher chance of developing breast cancer compared to the general population, the risk is not as high as with certain other inherited genetic conditions.
These genetic changes are present from birth and are inherited from a parent. Not everyone who inherits a moderate-penetrance gene variant will develop cancer, indicating that other genetic and environmental factors also play a role in disease development. Recognition of these genetic predispositions is important for identifying individuals who might benefit from tailored cancer screening and prevention strategies.
Symptoms & clinical features
Hereditary breast cancer itself does not present with specific symptoms beyond those typically associated with breast cancer. Symptoms generally develop when a tumour forms and may include a new lump or thickening in the breast or armpit, a change in the size or shape of the breast, skin changes (such as dimpling, redness, or puckering), nipple changes (like discharge or inversion), or persistent breast pain. These symptoms are not unique to hereditary forms of breast cancer and can also occur in sporadic, non-inherited cases.
For individuals with a moderate-penetrance genetic predisposition, the key 'symptom' is an increased risk of developing breast cancer. The age at which breast cancer might develop can vary, but it may occur at a younger age than in the general population for some individuals with these genetic changes [PMID:33658210]. Therefore, a family history of breast cancer, particularly at younger ages or involving multiple relatives, can be an important indicator that hereditary factors might be at play.
Video: Is cancer in your genes?
Affected organs
The primary organ affected by hereditary breast cancer associated with moderate-penetrance genes is the breast. Individuals with pathogenic changes in genes like ATM or CHEK2 primarily face an increased risk of developing breast cancer. Some research also suggests a potential, though often smaller, increase in the risk of other cancers, such as ovarian cancer or prostate cancer, particularly with certain ATM variants, but the most significant impact is on breast cancer risk [PMID:28806781].
The genetic changes themselves do not cause symptoms or affect organ function directly. Instead, they disrupt normal cellular processes, leading to an increased likelihood of abnormal cell growth in the breast tissue over time. The specific types of breast cancer can vary, but ductal carcinoma and lobular carcinoma are common.
Risks & severity
The severity of hereditary breast cancer can vary widely, as can the lifetime risk. For individuals with moderate-penetrance gene variants, the lifetime risk of developing breast cancer is increased compared to the general population, but generally less than for those with high-penetrance variants. For example, pathogenic variants in CHEK2 are associated with an elevated lifetime risk of breast cancer in women, exceeding the general population risk [PMID:33658210]. For ATM, the lifetime risk is also elevated, potentially in a similar range. These are estimates and individual risks can be influenced by specific variant type and family history.
Breast cancer associated with these genes can occur at various ages, though some studies suggest a slightly earlier average age of onset compared to sporadic breast cancer. The prognosis and treatment response are generally similar to sporadic breast cancers of the same stage and type. However, identifying a genetic predisposition can inform tailored screening protocols to detect cancer earlier and potentially lead to better outcomes. The risk associated with moderate-penetrance genes is often modulated by other factors, both genetic and environmental, making individual risk assessment complex.
Genetic causes
Hereditary breast cancer involving moderate-penetrance genes is caused by pathogenic variants in specific genes that play roles in DNA repair and cell cycle control. Two notable genes in this category are ATM and CHEK2.
The ATM gene (ATM serine/threonine kinase) is crucial for maintaining the integrity of the human genome. It coordinates the cell's response to DNA damage, particularly double-strand breaks. When a pathogenic variant occurs in ATM, this repair mechanism can be impaired, leading to an accumulation of genetic errors that can increase the risk of cancer development. The ATM protein acts as a central signalling molecule in the DNA damage response pathway.
The CHEK2 gene (checkpoint kinase 2) also plays a vital role in the cellular response to DNA damage. The CHEK2 protein acts as a critical checkpoint, deciding whether a cell should repair its DNA or undergo programmed cell death to prevent the propagation of mutations. Pathogenic variants in CHEK2 can compromise this critical decision-making process, allowing damaged cells to survive and potentially become cancerous. Both ATM and CHEK2 are therefore essential for preventing uncontrolled cell growth.
- ATM ATM serine/threonine kinaseThe ATM gene provides instructions for a protein vital for DNA repair and cell cycle regulation, impacting genomic stability, immune function, and neurological development.
- CHEK2 checkpoint kinase 2CHEK2 encodes checkpoint kinase 2, a tumour suppressor kinase that halts cell division when DNA damage is detected, allowing time for repair or triggering cell death if damage is irreparable.
Inheritance pattern
Hereditary breast cancer linked to moderate-penetrance genes follows an autosomal dominant inheritance pattern. This means that only one copy of the gene, out of the two copies an individual has, needs to have a pathogenic variant for the increased risk to be present.
If a parent has a pathogenic variant in a gene like ATM or CHEK2, each of their children has a 50% chance (one in two) of inheriting that same variant. This inheritance pattern applies equally to sons and daughters. Individuals who inherit the variant are at an increased risk of developing breast cancer, but inheriting the variant does not guarantee that cancer will develop. Family members who do not inherit the pathogenic variant do not have an increased genetic risk due to this specific gene.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Subtypes & variants
This page covers Hereditary breast cancer (moderate-penetrance genes) as a single condition. Several distinct variants and clinical subtypes are recognised in the literature - they share the underlying biology and broad management approach, but differ in severity, age of onset, or causative gene:
- CHEK2 CHEK2 OMIM 604373
CHEK2 truncating variants confer roughly 2- to 3-fold increased breast cancer risk and modestly increased risk of several other cancers (colorectal, prostate). Surveillance recommendations are typically less aggressive than for BRCA1/BRCA2 carriers.
- ATM ATM OMIM 114480
Heterozygous ATM variants confer roughly 2-fold increased breast cancer risk. Distinct from biallelic ATM disease (ataxia-telangiectasia). Surveillance with annual breast MRI is recommended for known carriers.
Diagnosis & testing
A diagnosis of hereditary breast cancer risk involving moderate-penetrance genes is typically made through genetic testing. This testing is usually considered for individuals with a personal or strong family history of breast cancer that suggests an underlying genetic predisposition. Referral to a clinical genetics service is often the first step in the diagnostic pathway.
Genetic testing typically involves a blood or saliva sample. DNA is extracted from the sample and analysed to identify pathogenic variants in relevant genes, such as ATM and CHEK2. The NHS Genomic Medicine Service offers genetic testing for inherited cancer predispositions, often through an R-code testing pathway (e.g., R151 for 'Constitutional Solid Tumour Susceptibility'). Genetic counsellors play a crucial role in explaining the testing process, interpreting results, and discussing the implications for the individual and their family. Clinical criteria, such as those used by NICE (National Institute for Health and Care Excellence), guide who is eligible for genetic testing based on their personal and family cancer history.
Management & lifestyle
Management for individuals identified with moderate-penetrance gene variants primarily focuses on personalised cancer screening and risk-reducing strategies. While there are no specific treatments for the genetic predisposition itself, the goal is to detect any potential cancers at an early, more treatable stage. This may include more frequent or intensive breast cancer screening, such as annual mammograms and MRI scans, often starting at a younger age than for the general population.
Risk-reducing medications, such as tamoxifen, may be considered for some women to lower breast cancer risk. Lifestyle modifications, including maintaining a healthy weight, regular exercise, and limiting alcohol intake, are also generally recommended as part of overall cancer prevention. Management decisions are made in consultation with specialists, including oncologists, breast surgeons, and clinical geneticists, within the NHS care pathway. Genetic counsellors provide ongoing support and information, helping individuals understand their risk and available options.
UK care pathway
In the UK, individuals suspected of having a hereditary breast cancer predisposition are typically referred to an NHS clinical genetics service. This service provides expert assessment, genetic counselling, and access to genetic testing. Testing for genes like ATM and CHEK2 falls under the NHS Genomic Medicine Service, often utilising specific R-codes from the National Genomic Test Directory (e.g., R151 for 'Constitutional Solid Tumour Susceptibility') to guide which tests are appropriate based on clinical criteria.
Genetic counsellors are key professionals within this pathway, offering detailed information about inheritance, risks, and the implications of genetic test results for both the individual and their wider family. They help patients navigate complex decisions about screening, risk reduction, and family planning. The overall care pathway aims to provide coordinated, evidence-based management tailored to the individual's specific genetic risk.
Frequently asked questions
What is the difference between moderate and high-penetrance genes?
High-penetrance genes, like BRCA1 and BRCA2, significantly increase the lifetime risk of developing cancer, often to 50% or more. Moderate-penetrance genes, such as ATM and CHEK2, also increase cancer risk, but to a lesser extent, typically raising the lifetime risk to a moderate level above the general population risk.
If I have a moderate-penetrance gene variant, will I definitely get cancer?
No, inheriting a moderate-penetrance gene variant does not mean you will definitely develop cancer. It means your lifetime risk is increased compared to the general population. Many individuals with these variants never develop cancer, as other genetic and environmental factors also influence disease development.
How does genetic testing for these genes work?
Genetic testing usually involves providing a blood or saliva sample. DNA from the sample is then analysed in a laboratory to look for specific pathogenic variants in genes like ATM and CHEK2. The results are typically discussed with a genetic counsellor who can explain their meaning for you and your family.
What screening recommendations are there for people with these gene variants?
Screening recommendations are personalised based on your specific gene variant, family history, and other risk factors. They may include starting breast cancer screening earlier than usual, with more frequent mammograms and potentially MRI scans. Your clinical team will discuss the most appropriate surveillance plan for you.
Can men also be affected by these moderate-penetrance gene variants?
Yes, men can also inherit these moderate-penetrance gene variants. While the primary concern is typically breast cancer in women, men with these variants may have a slightly increased risk of male breast cancer and potentially other cancers, depending on the specific gene. They can also pass the variant on to their children.