Moderate-risk genes on a panel result (CHEK2, ATM, and others)

Genetic testing for inherited cancer risk is now usually done as a panel, examining dozens of genes at once. Many of those genes are not the well-known ones. CHEK2 and ATM are the two most commonly found, and they belong to a group described as moderate-risk genes.

People who receive one of these results are frequently left in an uncomfortable position. They have been told they carry a gene change that raises their cancer risk, which sounds serious. But they are also told that surgery is not recommended, which sounds like it cannot be that serious after all. Neither message alone makes sense, and the explanation connecting them is often not given.

A moderate-risk result is a real finding with real consequences. Those consequences are mainly about screening: earlier and more sensitive tests to find cancer at a stage when it is highly treatable. They are usually not about removing healthy organs, because the level of risk does not justify an irreversible operation. This is a genuine and appropriate difference from genes such as BRCA1 and BRCA2, not a sign that your result is being taken less seriously.

This article is written for people who carry one of these gene changes, whether or not they have been diagnosed with cancer.

What “moderate risk” means

Inherited cancer genes are often sorted into three groups by how much they raise risk. The boundaries are approximate, and the underlying reality is a continuous scale rather than three boxes.

High-risk genes — Raise the risk of a specific cancer several times over, often to 40% or more across a lifetime. BRCA1, BRCA2, and the Lynch syndrome genes belong here. Risk-reducing surgery is often discussed.
Moderate-risk genes — Roughly double to quadruple the risk of a specific cancer, typically producing a lifetime risk somewhere between 20% and 40%. CHEK2 and ATM are the main examples. Management centers on enhanced screening.
Low-risk variants — Raise risk slightly, often by a few percent. Hundreds of these exist, most people carry many, and individually they do not change medical care.

To put these numbers in context, the average woman has roughly a 13% lifetime risk of breast cancer. A BRCA1 carrier has around 70%. A CHEK2 carrier has somewhere around 20% to 30%. The moderate-risk result is meaningfully above average and meaningfully below the high-risk genes, and the recommendations follow that position.

These categories are not fixed. PALB2 was considered moderate-risk for years and is now generally treated as high-risk, because better data showed the risk was higher than first estimated. Genes move between categories as evidence accumulates.

The gene name is also not the whole answer. Different changes within the same gene can carry different levels of risk. In CHEK2, a change called 1100delC, which shortens the protein, carries a breast cancer risk in the range of 20% to 30%, while a different change called I157T carries a risk generally below 20%. These two results appear on the report as the same gene but do not carry the same implications. Your doctor or genetic counselor can tell you which specific change was found.

What these genes do

Nearly all the moderate-risk cancer genes are involved in repairing damaged DNA. Cells sustain DNA damage constantly, and a cell that repairs it less efficiently accumulates errors faster, which over decades raises the chance one of them becomes cancerous.

ATM and CHEK2 work in the same chain of events. When DNA is broken clean through, ATM detects the break and signals CHEK2, which halts the cell from dividing until repair is complete. A change in either gene weakens this system.

These are tumor suppressor genes, and everyone carries two copies of each. A carrier is born with one working copy and one that does not work. That one copy is enough for normal life, which is why carriers are healthy, but it leaves every cell one step closer to losing the repair system entirely. Because the loss is partial rather than complete, the effect is smaller than for the high-risk genes, which is the biological reason these results carry moderate rather than high risk.

Cancers associated with the common moderate-risk genes

The figures below are approximate lifetime risks, with the general population risk alongside for comparison. They are ranges because published estimates vary considerably, for reasons explained in the next section.

CHEK2

CHEK2 is the moderate-risk gene found most often on panel testing. The clearest association is with breast cancer in women, with a lifetime risk generally in the range of 20% to 30%, compared with about 13% in the general population. Risk is higher for the protein-shortening changes such as 1100delC and lower for changes such as I157T.

Most CHEK2-associated breast cancers are estrogen receptor positive, which differs from the pattern seen with BRCA1. There is a modest increase in the risk of a second breast cancer in the other breast. Evidence also supports an increased risk of colorectal cancer, and a smaller increase in prostate cancer risk in men, though estimates vary and are less well established. Associations with thyroid and kidney cancer have been reported but are not firmly enough established to change management.

ATM

ATM is the second most commonly found. Lifetime risk of breast cancer in women is generally in the range of 20% to 30%, similar to CHEK2.

ATM also carries a modestly increased risk of pancreatic cancer, in the range of a few percent compared with under 2% in the general population, and an increased risk of prostate cancer in men, which may include a higher proportion of more serious disease. Reported associations with colorectal, stomach, and ovarian cancer are not currently strong enough to change screening recommendations.

There is one further point about ATM that often causes concern. If a person inherits a non-working copy from both parents, the result is a different and much more serious childhood condition called ataxia-telangiectasia, which affects balance, coordination, and the immune system. Carrying one non-working copy, which is what a moderate-risk result means, does not cause this condition and does not cause any symptoms. It becomes relevant only if both parents carry an ATM change, in which case each of their children has a one in four chance of inheriting two. This is uncommon, and a genetics service can advise where it applies.

Other genes in this group

Panels include other genes that fall into or near this category, including BARD1, RAD51C, RAD51D, BRIP1, and NBN. Several of these are associated more with ovarian than breast cancer, and management differs accordingly. If your report names a gene not covered above, the same general principles apply, but the specific recommendations should come from a genetics service, since the evidence base for each gene differs and is still developing.

How lifetime risk is estimated and why the numbers vary

Published risk figures for these genes vary more widely than for the high-risk genes, for several reasons.

Early studies overstated risk. As with all inherited cancer genes, the first studies looked at families identified because many members had cancer. Those families were selected for having a lot of cancer, so the risks calculated from them were higher than the risk faced by an average carrier. Later studies of large unselected populations produced lower figures.

Different changes within one gene carry different risks. This matters more for the moderate-risk genes than for the high-risk ones. A figure quoted for “CHEK2 carriers” is an average across changes that genuinely differ from one another.

Family history shifts the number substantially, and here it may matter more than the gene. Because the effect of a moderate-risk gene is smaller, the contribution of everything else, including family history and other genetic factors, makes up a larger share of a person’s total risk. A carrier with a mother and sister affected in their forties may have a considerably higher risk than a carrier with no family history at all, even with the identical gene change. This is why risk calculation tools that combine the gene result with family history are commonly used for these genes, and why two people with the same result can reasonably end up with different screening plans.

An increased risk is also not a certainty. A 25% lifetime risk means three in four carriers will never develop that cancer. The risk is meaningfully raised; it can be acted on through screening, and it is far from inevitable.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This is a positive result and the basis for the management described below. The report should name the specific change.
Variant of uncertain significance — A change was found but its effect is unknown. This is not a positive result, is managed as though negative with screening guided by family history, and is never a basis for preventive surgery. These are especially common in the moderate-risk genes, because panels test many of them and they are less thoroughly characterized than BRCA1 and BRCA2. Our article on variants of uncertain significance covers this result in detail.
Benign or likely benign variant — A harmless difference, usually not reported.
No variant identified — No change was found in the genes tested.

What the result means

A pathogenic or likely pathogenic variant in a moderate-risk gene means an increased lifetime risk of specific cancers, a screening plan that begins earlier and uses more sensitive tests than usual, and a 50% chance that each of your children, siblings, and parents carries the same change.

A negative result means two different things depending on the situation:

True negative — A specific change is already known in your family and you tested negative for that exact change. You did not inherit it and cannot pass it on.
Uninformative negative — No change has been identified in anyone in your family. This rules out the genes tested but does not rule out an inherited cause, and screening continues based on family history.

Germline versus somatic changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. That is what this article is about.

A somatic change arises within a tumor during life, exists only in the cancer cells, and cannot be inherited.

This distinction matters here because ATM and CHEK2 appear frequently on tumor sequencing panels, which test the cancer rather than inherited DNA. A tumor report naming one of these genes does not by itself mean the change is inherited. Confirming that requires a separate test on blood or saliva, and a meaningful proportion do turn out to be germline. If a tumor panel has reported one of these genes and nobody has discussed germline testing with you, you can ask whether it would be appropriate.

Screening and risk reduction

What the care team considers depends on the gene, your sex, and your family history. The consistent theme across all of these genes is that screening rather than surgery is the main tool.

Breast screening

For women carrying a CHEK2 or ATM change, annual breast MRI is generally offered from around age 30 to 35, with annual mammography added from age 40. The threshold for adding MRI to routine screening is a lifetime risk of about 20%, which most carriers of these genes meet.

Screening of this kind has a substantial effect. Modeling studies estimate that annual MRI starting at 30 to 35, with mammography added at 40, could reduce breast cancer deaths by more than half for women with ATM, CHEK2, or PALB2 changes. Screening is the intervention that does the work for these genes, and attending it consistently matters.

Where the specific change carries a lower risk, such as CHEK2 I157T, the calculated lifetime risk may fall below the threshold at which MRI is recommended, and mammography alone may be appropriate. This is one of the practical reasons the specific change matters.

Risk-reducing mastectomy

Preventive removal of both breasts is not routinely recommended for carriers of moderate-risk genes, and current guidelines do not support offering it on the basis of the gene result alone. The reasoning is proportionality: the operation is irreversible and has permanent consequences, and at this level of risk, screening finds cancers early enough that the balance does not favor surgery.

It is not forbidden, and it may be considered where other factors point the same way, such as a strong family history, a previous breast cancer, or a personal risk estimate that is high once everything is taken into account. But the decision should rest on the whole picture rather than on the gene result alone.

Studies have found that carriers of moderate-risk genes undergo preventive mastectomy more often than guidelines support, including carriers of the lower-risk CHEK2 changes. If surgery is being discussed primarily because of a moderate-risk gene result, you can ask what your estimated risk is once family history is included, and request input from a genetics service.

Other screening

Pancreatic — For ATM carriers, pancreatic surveillance with MRI and endoscopic ultrasound is generally offered only to those who also have a family history of pancreatic cancer, rather than to all carriers.
Prostate — Men carrying either gene are generally offered a discussion about starting PSA screening earlier than usual, often from around age 40.
Colorectal — For CHEK2, some guidelines suggest starting colonoscopy earlier than the general population, commonly around age 40, particularly with a family history of colorectal cancer. Standard screening is generally advised for ATM.
Ovarian — Neither CHEK2 nor ATM is currently considered to raise ovarian cancer risk enough to warrant removing the ovaries. Some other genes in this group, including RAD51C, RAD51D, and BRIP1, do.

If cancer is diagnosed

Unlike the high-risk genes, moderate-risk results usually do not change cancer treatment, and PARP inhibitors are not approved on the basis of a CHEK2 or ATM result in most settings. Clinical trials in this area are ongoing, and your oncologist can tell you whether any are open to you.

People carrying an ATM change sometimes ask whether radiation therapy is safe for them, because the gene is involved in repairing the kind of DNA damage that radiation causes. The severe radiation sensitivity seen in ataxia-telangiectasia occurs in people with two non-working copies. For carriers of a single change, studies of breast radiation therapy have not shown a clear excess of serious side effects, and radiation is not generally withheld. A radiation oncologist can discuss this in your specific situation.

Testing family members

These genes are inherited in an autosomal dominant pattern, meaning a single altered copy is enough. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change, and it passes through fathers exactly as it does through mothers.

Once a specific change is identified, relatives can be tested for that exact change through cascade testing, which is simpler, cheaper, and gives a clear yes or no.

There is one point that applies particularly to moderate-risk genes. Because the risk conferred by the gene is smaller, a relative’s own family history contributes proportionally more to their total risk. A relative who tests positive may or may not cross the threshold at which enhanced screening is recommended, depending on the rest of their history. Some will, and some will not. Relatives should therefore expect their result to be interpreted alongside their own family history rather than treated as a single answer, and a risk calculation is often part of that conversation.

Testing is usually offered to adult relatives from around age 18 to 25, since screening for these genes does not begin before the late twenties or thirties. For ATM, a genetics service may also discuss testing a partner if a couple is planning a family, because of the childhood condition that arises when a child inherits two non-working copies.

What happens next

For someone with a cancer diagnosis, a moderate-risk result usually does not change the treatment of that cancer. What it adds is a screening plan for the other organs at risk, a consideration for the opposite breast in breast cancer, and referral for family testing.

For a carrier who has not had cancer, the work is establishing an appropriate screening schedule and arranging cascade testing for relatives. A risk calculation combining the gene result with family history is often the most useful next step, since it determines which screening applies.

Because the evidence for these genes is still developing and recommendations have changed more than once, reconnecting with the genetics service every few years is worthwhile. What was advised when you were tested may not be what is advised now.

Questions to ask your doctor

Which gene, and which specific change, was found?
Does that particular change carry a higher or lower risk than others in the same gene?
Taking my family history into account, what is my estimated lifetime risk?
Does my estimated risk meet the threshold for breast MRI screening?
At what age should my screening start, and how often?
Do I need screening for any cancer other than breast cancer?
Is risk-reducing surgery appropriate in my case, or is screening the better option?
If surgery is being discussed, would that recommendation be the same without this gene result?
If I have cancer now, does this result change my treatment or open a clinical trial?
If I carry an ATM change, is radiation therapy safe for me?
Which of my relatives should be offered testing, and can you provide a letter for them?
Will a relative who tests positive necessarily need extra screening?
How often should I reconnect with the genetics service as evidence changes?