Breast Cancer

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: ATM (HGNC:795) CHEK2 (HGNC:16627)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 06/04/2025
• Curation Status: Released - Under Revision

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
ATM	hereditary breast carcinoma (0016419)	114480	Moderate Actionability
CHEK2	hereditary breast carcinoma (0016419)	114480	Moderate Actionability

Actionability Assertion Rationale

• Assertion for ATM: Despite more recent data on likelihood, all experts agreed with the assertion computed according to the rubric. Further information is needed regarding the specific effectiveness in patients with ATM variants (current scoring is extrapolated from patients with variants in BRCA1/2), as well as the penetrance in individuals with the ATM 7271T-G missense variant. Assertion for CHEK2: Despite more recent data on likelihood, all experts agreed with the assertion computed according to the rubric. Further information is needed regarding the specific effectiveness in patients with CHEK2 variants (current scoring is extrapolated from patients with variants in BRCA1/2).

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Breast Cancer (ATM) / Chemoprevention	2	2A	2B	2	8AB
Breast Cancer (ATM) / Surveillance	2	2A	2B	3	9AB
Breast cancer (CHEK2) / Chemoprevention	2	2C	2B	2	8CB
Breast cancer (CHEK2) / Surveillance	2	2C	2B	3	9CB

Severity of Outcome

Prevalence of the Genetic Condition

For women, lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it. Among a sample of women with non-metastatic breast cancer 1% had an ATM pathogenic variant, and 8.5% of women with early-onset breast cancer were found to have an ATM pathogenic variant. Among familial breast cancer families without a BRCA1/2 pathogenic variant, CHEK2 pathogenic variants have been detected in 5% of cases.

Clinical Features (Signs / symptoms)

ATM encodes the ATM protein, which is involved in cell cycle control and DNA repair. CHEK2 codes for the CHEK2 protein which acts at a tumor suppressor in blocking cell proliferation and initiating DNA repair. ATM and CHEK2 pathogenic variants are associated with an increased risk of breast cancer.

Natural History (Important subgroups & survival / recovery)

The presence of an ATM pathogenic variant has been linked to reduced overall survival in individuals with breast cancer (HR: 5.6; 95% CI: 2.6 to 12.0). ATM mutation carriers (heterozygotes) have been found to have a reduced life expectancy of 7-8 years less than family members who are non-carriers, with higher relative risks of mortality including cancer mortality. The relative risk for developing breast cancer for females with heterozygous ATM pathogenic variants is estimated to be 3.0 (95% CI: 2.1-4.5), with higher risks for those under the ages of 45-55. Variables that appear to affect breast cancer risk in ATM heterozygotes include age, position within the pedigree, and previous exposure to radiation, age at first childbirth, smoking, and specific ATM pathogenic variant. The presence of a CHEK2 pathogenic variant has been linked to reduced overall survival in individuals with breast cancer (HR: 6.9; 95% CI: 3.1 to 15.0).Most studies of breast cancer risk in CHEK2 heterozygotes have involved specific variants. Case-control studies indicate that the 1100delC variant (NM_007194.3(CHEK2):c.1100delC (p.Thr367Metfs)) is associated with increased risk for breast cancer, even in women unselected for family history (OR=2.34; 95% CI: 1.72–3.20; p<0.001), and a significantly increased risk of developing ER-positive breast cancer (OR=2.55; 95% CI: 2.10–3.10; p<0.001). Results from a meta-analysis showed that the missense variant I157T (NM_007194.3(CHEK2):c.470T>C (p.Ile157Thr)) is associated with increased risk for breast cancer (OR=1.58; 95% CI: 1.42–1.75; p<0.001).

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Information on the prevalence of ATM or CHEK2 pathogenic variants in the general population was not identified.

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

The penetrance of breast cancer in individuals with a pathogenic variant in ATM is estimated to be 6% (95% CI: 4.6-7.4%) by age 60 and 33 to 38% (95% CI: 24.6-40.4%) by age 80. Based on published relative risks, the lifetime risk may vary between 24 and 55%. For those under age 50, the risk is estimated to be 16% and may vary between 11 and 19%. The lifetime risk for those with an ATM 7271T-G missense mutation is 69%, which is similar to the lifetime risk for BRCA1/2 mutation carriers.

Tier 1

5-39 %

A rough estimate of the lifetime risk (based on ORs from case-control studies aggregated with the risk in women in the general population) found that among those with familial breast cancer, women heterozygous for the CHEK2 1100delC variant have a cumulative breast cancer risk of 37% (95% CI: 26-56%) by age 70.

Tier 1

5-39 %

The estimated risk of breast cancer by age 80 for those with a CHEK2 pathogenic variant is 29%, and estimates of cumulative lifetime risk for those with a family history of breast cancer range from 28% to 37%.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

>3

A meta-analysis of four cohort studies of breast cancer for females with a heterozygous ATM pathogenic variant found a pooled relative risk of 3.0 (95% CI: 2.1-4.5). For women under age 45-55 the pooled relative risk was 7.0 (95% CI: 4.1-11.7).

Tier 1

>3

Among those with a familial breast cancer, women heterozygous for the CHEK2 1100delC variant have a relative risk of breast cancer of 4.8 (95% CI: 3.3-7.2).

Tier 1

>3

The estimated relative risk of breast cancer for those with a CHEK2 truncating mutation is 3.0 (90% CI: 2.6-3.5).

Tier 3

Expressivity

No information identified.

Intervention Effectiveness

Patient Management

While no chemoprevention recommendations were identified for patients with ATM or CHEK2 pathogenic variants specifically, guidelines based on lifetime risk levels similar to those associated with ATM or CHEK2 pathogenic variants state that healthcare professionals within a specialist genetics clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer. No direct evidence on the effectiveness of chemoprevention in patients with ATM or CHEK2 pathogenic variants was detected. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1, BRCA2, and/or TP53 pathogenic variant. Among these patients:

- High quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials has subsequently been published; this study found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). - Low quality evidence from a single randomized trial suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35; 95% CI: 0.18-0.70)

Tier 1

There are mixed recommendations for whether women should be offered risk-reducing mastectomy. One guideline states that women with an ATM pathogenic variant do not rise to the level of risk that would justify surgery.

Tier 1

A second guideline recommends that women with a ATM pathogenic variant could consider risk-reducing mastectomy based on their family history. For women with a CHEK2 pathogenic variant, the evidence is insufficient for risk-reducing mastectomy, women should be managed based on family history.

Tier 2

No direct evidence on the effectiveness of risk-reducing surgery in patients with ATM or CHEK2 pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1 and BRCA2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women.

Tier 1

Surveillance

Females heterozygous for an ATM pathogenic variant are advised to have earlier surveillance for breast cancer starting at age 40. The modality of screening varies by guideline, with one guideline recommending screening with annual mammography from 40 to 50 years of age followed by screening from age 50-75 in the general population screening program.

Tier 1

A second guideline recommended annual mammography starting at age 40 and breast MRI with contrast may be considered.

Tier 2

Female carriers of the ATM 7271T-G missense mutation (NM_000051.3(ATM):c.7271T>G (p.Val2424Gly)) are advised to have an annual MRI starting at the age of 25 combined with annual mammography from age 30 onwards (as routinely offered to all BRCA1/2 mutation carriers that are at similar risk).

Tier 1

Heterozygous female carriers of a CHEK2 pathogenic variant are advised to undergo screening with annual mammography starting at age 40 and may consider screening with breast MRI.

Tier 2

No direct evidence on the effectiveness of breast cancer surveillance in patients with ATM or CHEK2 pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77]).

Tier 1

Circumstances to Avoid

Nature of Intervention

Nature of Intervention

The interventions identified in this report include screening tests, prophylactic surgery to remove target organs, and medications with potential side effects.

Context: Adult

Chance to Escape Clinical Detection

Given that women with ATM or CHEK2 pathogenic variants have an increased risk of breast cancer at younger ages than the general population it is possible that cases could be missed by current screening programs.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			ATM			114480	0016419
CHEK2			114480	0016419

References List

Liu C, Chang H, Li XH, Qi YF, Wang JO, Zhang Y, Yang XH. (2017) Network Meta-Analysis on the Effects of DNA Damage Response-Related Gene Mutations on Overall Survival of Breast Cancer Based on TCGA Database. Journal of cellular biochemistry. 118(1097-4644):4728-4734.

Marabelli M, Cheng SC, Parmigiani G. (2016) Penetrance of ATM Gene Mutations in Breast Cancer: A Meta-Analysis of Different Measures of Risk. Genetic epidemiology. 40(5):425-31.

National Collaborating Centre for Cancer (UK). (2013) . Familial Breast Cancer: Classification and Care of People at Risk of Familial Breast Cancer and Management of Breast Cancer and Related Risks in People with a Family History of Breast Cancer.

National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian (version 2.2017). Publisher: National Comprehensive Cancer Network (2016) Accessed: 2017-03-24. URL: http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf

Nelson HD, Fu R, Goddard K, Mitchell JP, Okinaka-Hu L, Pappas M, Zakher B. (2013) . Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation.

van Os NJ, Roeleveld N, Weemaes CM, Jongmans MC, Janssens GO, Taylor AM, Hoogerbrugge N, Willemsen MA. (2016) Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clinical genetics. 90(2):105-17.

Weischer M, Bojesen SE, Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. (2008) CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 26(4):542-8.