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ATM-Related Cancer Predisposition

, MD, PhD, , MD, , MD, , MD, PhD, and , MD.

Author Information and Affiliations

Initial Posting: .

Estimated reading time: 39 minutes

Summary

Clinical characteristics.

ATM-related cancer predisposition is characterized by a moderately increased risk of female breast cancer, exocrine pancreatic cancer, prostate cancer, and gastric cancer. Modest associations for other cancers (ovarian, colorectal, and melanoma) have been reported, but larger studies are required to confirm these associations.

Diagnosis/testing.

The diagnosis of ATM-related cancer predisposition is established in a proband with a heterozygous germline pathogenic variant in ATM identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard cancer treatment per oncologist and other specialists. To date, there is insufficient evidence to recommend specific cancer treatments for individuals with ATM-related cancer predisposition. When indicated, radiotherapy can be used in individuals with ATM-related cancer predisposition.

Prevention of manifestations: Bilateral risk-reducing mastectomy and/or bilateral salpingo-oophorectomy can be considered in the context of a personalized risk assessment including family history using a shared decision-making approach with the affected individual. Endocrine risk-reducing therapies (e.g., tamoxifen, raloxifene, or anastrozole) can be considered in the context of family history and personalized risk estimates.

Surveillance: In females: breast self-examination training at the time of diagnosis; annual mammogram beginning at age 40 years; annual breast MRI beginning at age 30-35 years (recommendations regarding age to start breast surveillance and use of breast MRI vary by country). The recommendations for prostate and pancreatic cancer screening vary by location.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic male and female at-risk relatives of an individual with ATM-related cancer predisposition in order to identify family members who may benefit from appropriate surveillance and early diagnosis and treatment of ATM-related cancer.

Genetic counseling.

ATM-related cancer predisposition is inherited in an autosomal dominant manner. The vast majority of individuals with a germline ATM pathogenic variant inherited the pathogenic variant from a parent. The parent with the pathogenic variant may or may not have had a cancer diagnosis depending on the penetrance of the variant, the sex and age of the parent, cancer risk reduction in the parent as a result of screening or prophylactic surgeries, or early death of the parent. Unless the reproductive partner of a proband also has a germline ATM pathogenic variant(s), the offspring of an individual with ATM-related cancer predisposition have a 50% chance of inheriting the pathogenic variant and having ATM-related cancer predisposition. If the reproductive partner of a proband has a germline ATM pathogenic variant(s), offspring are at risk of inheriting biallelic ATM pathogenic variants and having ataxia-telangiectasia. Once the ATM pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for ATM-related cancer predisposition have been published.

Suggestive Findings

ATM-related cancer predisposition should be suspected in probands with the following clinical and laboratory findings and family history.

Clinical findings

  • Estrogen receptor (ER)–positive breast cancer, particularly in a proband with a family history of breast, prostate, pancreatic, and/or gastric cancer in close relatives
  • Prostate cancer, particularly young onset and/or aggressive disease in a proband with a family history of breast, prostate, and/or pancreatic cancer in close relatives
  • Exocrine pancreatic cancer, such as adenocarcinoma, but also including acinar cell carcinoma diagnosed at any age
  • Results from a risk assessment model (e.g., CanRisk) incorporating family history of cancers, personal risk factors, and ER status of breast cancer that indicates an increased likelihood of identifying an ATM pathogenic (or likely pathogenic) variant

Laboratory findings. Identification of an ATM pathogenic variant on tumor tissue testing

Note: In an analysis of 45,472 non-hypermutated solid malignancies from individuals treated at a single oncology center, approximately half of filtered ATM variants present in tumor tissue (52.6%, 328/623) were also present in the germline. Variants filtered for inclusion in the overall analyses were those (1) with minor allele frequency (MAF) <1%, (2) with tumor observed variant allele frequency (VAF) >30% (single-nucleotide variants) or >20% (small insertions/deletions), and (3) predicted to result in protein truncation and/or classified as pathogenic / likely pathogenic [Kuzbari et al 2023]. The proportion of pathogenic variants identified in tumor tissue that were also present in the germline (constitutional) varied by tumor type. For example, 72.6% (53/73) of ATM pathogenic variants identified in breast cancer were also found in the germline, compared to 33.3% (24/72) of ATM pathogenic variants detected in colorectal cancers [Kuzbari et al 2023].

Family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). However, as ATM is associated with intermediate penetrance, the presence of individuals in a family without cancer is common and a typical autosomal dominant pattern of inheritance is often not observed. Individuals with ATM-related cancer predisposition can also be identified due to a family history of the autosomal recessive disorder ataxia-telangiectasia.

Establishing the Diagnosis

The diagnosis of ATM-related cancer predisposition is established in a proband with a heterozygous germline pathogenic (or likely pathogenic) variant in ATM identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology (AMP) variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous ATM variant of uncertain significance does not establish or rule out the diagnosis. (3) Guidelines from the Evidence-Based Network for Interpretation of Germline Mutant Alleles (ENIGMA) group for standardized reporting of germline cancer susceptibility variants suggest that only variants associated with a twofold or greater risk should be clinically reported [Spurdle et al 2019]. Loss-of-function variants and ATM variant c.7271T>G should be reported, but other missense variants are often associated with a smaller increased risk of breast cancer (see Genotype-Phenotype Correlations). (4) Identification of low-level mosaicism for an ATM pathogenic variant in leukocytes is most suggestive of a postzygotic (acquired) pathogenic variant associated with clonal hematopoiesis of indeterminate potential (CHIP) due to aging, cytotoxic therapies, an underlying hematologic malignancy or premalignancy, or circulating tumor cells [Slavin et al 2019]. (5) Variants at allele frequencies in the heterozygous range may also be acquired, and further testing of different tissues to determine if a pathogenic variant is constitutional or somatic should be guided by clinical evaluation [Sutcliffe et al 2022].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

Single-gene testing. Sequence analysis of ATM is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

A multigene panel that includes ATM and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other cancer predisposition syndromes, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. Note: Several deep intronic ATM pathogenic variants have been identified in individuals with ataxia-telangiectasia (c.5763-1050A>G, c.2639-384A>G, c.2839-579_2839-576delAAGT, c.3994-159A>G, and c.1803-270T>G) that may not be detected on exome sequencing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

ATM-Related Cancer Predisposition: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
ATM Sequence analysis 390%-95% 4
Gene-targeted deletion/duplication analysis 55%-10% 4, 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

ATM intragenic deletions and duplications have been reported in individuals with ataxia-telangiectasia [Cavalieri et al 2008, Nakamura et al 2012, Schon et al 2019]. Data also derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.

6.

The proportion of ATM pathogenic variants that are large intragenic deletions and duplications varies by population.

Clinical Characteristics

Clinical Description

ATM-related cancer predisposition is characterized by an increased risk of female breast cancer [Dorling et al 2021, Hall et al 2021, Hu et al 2021, Rowlands et al 2024], pancreatic cancer [Hu et al 2018, Hall et al 2021, Hsu et al 2021, Gardiner et al 2022], prostate cancer [Hall et al 2021, Karlsson et al 2021, Darst et al 2023], and gastric cancer [Hall et al 2021, Zeng et al 2022, Usui et al 2023]. Modest associations for other cancers (ovarian, colorectal, and melanoma) have been reported [Hall et al 2021], but larger studies are required to confirm these associations. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

ATM-Related Cancer Predisposition: Frequency of Select Features

FeatureGeneral Population Risk to Age 80 YearsCancer Risk to Age 80 Years in ATM Heterozygotes 1Odds Ratios
Female breast cancer ~12%
  • 2.16 (95% CI: 1.93-2.41) for all germline pathogenic variants 6
  • 2.10 (95% CI: 1.71-2.57) for truncating variants 4
  • 1.82 (95% CI: 1.46-2.27) 3
Prostate cancer ~12%
  • Risk not well defined for truncating variants
  • 43% for c.7271T>G 5
  • 4.44 (95% CI: 2.0-9.5) 7
  • 2.58 (95% CI: 1.93-3.44) 8
Pancreatic cancer ~1%-2%9.5% (95% CI: 5.0-14.0) 9
  • 4.21 (95% CI: 3.24-5.47) 8
  • 6.5 (95% CI: 4.5-9.5) 9
  • 5.7 (95% CI: 4.4-7.3) 10
  • 3.44 (95% CI: 2.58-4.60) 11
  • 4.44 (95% CI: 2.66-7.40) 12
1.

Individual cancer risk will be modified by other factors such as family history, lifestyle factors, and hormonal factors.

2.

Not well defined

3.

Hu et al [2021]; included loss-of-function variants (nonsense, frameshift, consensus splice sites), first codon missense variants, and variants classified as pathogenic in ClinVar, including large deletions/duplications

4.
5.
6.
7.
8.
9.
10.
11.
12.

Breast cancer. Large case-control studies have reported a moderately increased risk of breast cancer for women with a heterozygous germline ATM pathogenic variant. A Breast Cancer Association Consortium study reported an odds ratio (OR) of 2.10 (95% CI: 1.71-2.57) for truncating variants, based on 294 affected women and 150 controls [Dorling et al 2021]. There was no significant difference in effect size for truncating variants in ATM in European women and Asian women. Another large study (CARRIERS) reported an OR of 1.82 (95% CI: 1.46-2.27) for all individuals with a germline ATM pathogenic variant (see Table 2, footnote 3), based on 253 affected women and 134 controls [Hu et al 2021].

The risk is predominantly for estrogen receptor (ER)–positive breast cancer. There is no evidence of increased risk of ER-negative breast cancer [Dorling et al 2021, Hu et al 2021]. The OR was stable with increasing age, with the OR in women younger than age 40 years similar to those older than age 60 years [Dorling et al 2021]. There is conflicting evidence about whether ER-positive, HER2-negative breast cancers [Mavaddat et al 2022] or ER-positive, HER2-positive breast cancers [Couch et al 2017] are most strongly associated with ATM-related cancer predisposition. In a study of 24 breast cancers in women with a heterozygous germline ATM pathogenic variant, nearly 80% of tumors showed loss of heterozygosity of the wild type allele, but none showed appreciable defects in homologous recombination repair [Weigelt et al 2018].

There is limited information available regarding outcomes following breast cancer diagnosis in women with ATM-related cancer predisposition. A retrospective study of 286 women with stage I-III breast cancer, including eight with ATM-related cancer predisposition, did not find significant differences in overall survival, locoregional recurrence, or disease-specific death between those with a germline ATM pathogenic variant and those without [Chapman et al 2022].

Contralateral breast cancer. An increased risk for contralateral breast cancer has not been observed for women with ATM-related cancer predisposition [Dorling et al 2021, Hu et al 2021, Morra et al 2023, Yadav et al 2023]. This could be due to the modest numbers of women with ATM-related cancer predisposition in reported studies (~200-300 women with a germline ATM pathogenic variant and a diagnosis of breast cancer). As ATM-related breast cancers are predominantly ER-positive, it may also be that adjuvant hormone therapy for the primary cancer is particularly effective in preventing contralateral breast cancer.

Prostate cancer. A large case-control study of 5,560 individuals with prostate cancer and 3,353 controls showed that ATM germline pathogenic variants are associated with an increased lifetime risk of prostate cancer (OR = 4.4, 95% CI: 2.00-9.50), as well as a higher risk of early-onset disease [Karlsson et al 2021]. A study using data from a single reference laboratory reported an OR for prostate cancer of 2.58 (95% CI: 1.93-3.44) in those with ATM-related cancer predisposition [Hall et al 2021].

The proportion of germline ATM pathogenic variants is higher in men with aggressive prostate cancer than nonaggressive prostate cancer. A recent study of 9,185 men with aggressive prostate cancer and 8,361 men with nonaggressive prostate cancer found a higher frequency of germline ATM pathogenic variants in those with aggressive prostate cancer (1.6%) and metastatic prostate cancer (1.9%) compared to those with nonaggressive prostate cancer (0.7%) [Darst et al 2023]. A study of homologous recombination deficiency scores in prostate cancers found that the score was significantly lower in ATM-related cancer predisposition compared to men with a germline BRCA2 pathogenic variant [Lotan et al 2021].

Current evidence indicates that conventional therapies can be effective in metastatic prostate cancer in men with ATM-related cancer predisposition. Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) olaparib and talazoparib with enzalutamide are approved for metastatic castration-resistant prostate cancer in men with germline pathogenic variants in any of 12 homologous recombination repair genes, including ATM. The data that led to approval were predominantly based on BRCA2-associated prostate cancer. There is limited evidence of efficacy in ATM-related cancer predisposition. The combination of talazoparib with enzalutamide versus enzalutamide alone as first-line treatment in those with metastatic castration-resistant prostate cancer did not show a significant benefit in men with ATM-related cancer predisposition (reviewed in Pal et al [2025]).

Pancreatic cancer. Germline ATM pathogenic variants are one of the most common genetic causes of hereditary pancreatic ductal adenocarcinoma [Astiazaran-Symonds & Goldstein 2021]. A recent study of families with pancreatic cancer reported a relative risk (RR) of 6.5 (95% CI: 4.5-9.5) in ATM heterozygotes compared to those without a germline ATM pathogenic variant. The cumulative risk of pancreatic cancer was 1.1% (95% CI: 0.8-1.3) by age 50 years, 6.3% (95% CI: 3.9-8.7) by age 70 years, and 9.5% (95% CI: 5.0-14.0) by age 80 years in those with ATM-related cancer predisposition. The average age at diagnosis of pancreatic cancer was 64 years (range: 31-98 years) in those with ATM-related cancer predisposition [Hsu et al 2021]. Another study comparing individuals with pancreatic cancer to population controls from the Exome Aggregation Consortium dataset (excluding cancer cases from the Cancer Genome Atlas) found an RR of 5.7 (95% CI: 4.4-7.3) [Hu et al 2018]. A study of data from a single reference laboratory reported an increased risk of pancreatic ductal carcinoma in those with an ATM pathogenic variant compared to controls with an OR of 3.44 (95% CI: 2.58-4.60) [Gardiner et al 2022]. Another study from the same reference laboratory reported an increased risk of any pancreatic cancer in those with an ATM pathogenic variant compared to controls with an OR of 4.21 (95% CI: 3.24-5.47) [Hall et al 2021].

Studies of pancreatic adenocarcinomas in individuals with ATM-related cancer predisposition have shown loss of heterozygosity of the wild type allele in most instances. The germline instability score was relatively low, suggesting that pancreatic cancer in those with ATM-related cancer predisposition is less likely to be responsive to therapies directed at homologous repair–defective tumors [Pal et al 2025].

A prospective study of 3,078 individuals with pancreatic adenocarcinoma found that those with a germline pathogenic variant in a homologous recombination repair gene (including 65 with ATM) were significantly younger, more likely to have metastatic disease at diagnosis, and had longer survival [Yadav et al 2020].

There is anecdotal evidence of partial or stable response to oxaliplatin-based chemotherapy in those with ATM-related cancer predisposition. There is limited evidence of response to olaparib [Pal et al 2025].

Other cancers – gastric, ovarian, colorectal, and melanoma. There is limited evidence for an association of ATM with other cancers. With respect to gastric cancer, a study using data from a single reference laboratory reported moderately increased risk of gastric adenocarcinoma in individuals with ATM-related cancer predisposition, with an OR of 2.97 (95% CI: 1.66-5.31) [Hall et al 2021]. A large study from BioBank Japan including 10,426 people with gastric cancer and 38,153 controls found a moderate to high risk of gastric cancer in ATM heterozygotes with an OR of 5.50 (95% CI: 3.82-7.90) [Usui et al 2023]. The association appeared to be modulated by exposure to H pylori. A phenome-wide association study of 214,020 participants from three cohorts compared participants with and without germline pathogenic variants in ATM and demonstrated an OR of 4.27 (95% CI: 2.35-7.44) [Zeng et al 2022] for gastric cancer.

Modest associations for other cancer types (OR <2) in ATM heterozygotes have been reported. A study using data from a single reference laboratory reported an OR of 1.57 (95% CI: 1.35-1.83) for ovarian cancer, 1.49 (95% CI: 1.24-1.79) for colorectal cancer, and 1.46 (95% CI: 1.18-1.81) for melanoma [Hall et al 2021]. Larger studies are required to determine if there is an increased risk of ovarian cancer, colorectal cancer, melanoma, or other cancers in those with ATM-related cancer predisposition.

Genotype-Phenotype Correlations

Specific ATM missense variants predispose to a higher cancer risk compared to the risk associated with other ATM pathogenic variants (with breast cancer OR approximately 4- to 6-fold compared to population risk).

The variant c.7271T>G is associated with a breast cancer risk of 52% by age 70 [Bernstein et al 2006] and 60% by age 80 [Goldgar et al 2011]. Data from a single reference laboratory also found a higher breast cancer risk, with an OR of 3.76 (95% CI: 2.76-5.12) in women with ATM pathogenic variant c.7271T>G compared to an OR of 2.03 (95% CI: 1.89-2.19) for those with any ATM pathogenic variant [Hall et al 2021]. Data from the UK Biobank and Breast Cancer Association Consortium (BCAC) demonstrated that the magnitude of increased risk of invasive breast cancer associated with c.7271T>G was similar in those from the UK Biobank (RR = 4.57, 95% CI: 2.25-9.30, P = 0.000027) and individuals in the BCAC (OR = 4.11, CI 95%: 2.05-8.26, P = 0.000069). Furthermore, analysis of individuals in the UK Biobank showed that c.7271T>G was associated with an increased risk of prostate cancer (RR = 4.84, CI 95%: 2.27-10.33, P = 0.0000454) and diagnosis of any cancer in males and females (RR [males] = 2.79, CI 95%: 1.33-5.85, P = 0.0066; RR [females] = 3.15, CI 95%: 1.49-6.63, P = 0.0026). Based on these findings, individualized management of individuals heterozygous for ATM pathogenic variant c.7271T>G was recommended [Mukhtar et al 2025].

Finnish founder pathogenic variant c.7570G>C is also reported to be associated with a high risk of breast cancer (OR = 8.5, 95% CI: 1.04-62.46) [Kankuri-Tammilehto et al 2023].

Note: The CanRisk online tool for calculating an individual's future risk of developing breast, ovarian, or prostate cancer uses risk estimates derived from data on truncating variants in ATM; therefore, CanRisk would underestimate the cancer risk associated with higher-penetrance ATM missense variants (e.g., c.7271T>G).

Penetrance

The penetrance of breast and other cancers associated with pathogenic variants in ATM is less than 100% (see Table 2).

Nomenclature

Terms that may be used to refer to individuals with ATM-related cancer predisposition include ataxia-telangiectasia heterozygote, ataxia-telangiectasia carrier, AT carrier, ATM mutation carrier, and ataxia-telangiectasia mutated heterozygote.

Prevalence

A meta-analysis of population-based germline breast cancer association studies (BRIDGES, CARRIERS, and UK Biobank) found that an ATM pathogenic variant was present in 767 of 101,397 (0.76%) affected individuals and 1,090 of 312,944 (0.35%) controls [Rowlands et al 2024]. The highest frequency for an ATM heterozygous pathogenic variant, based on data from gnomAD v3.1, was 0.00706 (1/142) in Latino / admixed American populations, with a frequency of 0.00280 (1/357) in African / African American populations, 0.00230 (1/434) in Ashkenazi Jewish populations, 0.00270 (1/370) in East Asian populations, 0.00361 (1/277) in non-Finnish European populations, and 0.00083 (1/1,204) in South Asian populations [Schmitz et al 2022, Chen et al 2024]. Several ATM pathogenic variants are reported to be recurrent in specific populations and may represent founder effects (see Table 5).

Differential Diagnosis

Cancer predisposition syndromes of interest in the differential diagnosis of ATM-related cancer predisposition are listed in Table 3.

Table 3.

ATM-Related Cancer Predisposition: Genetic Differential Diagnosis

Gene(s)Cancer Susceptibility SyndromeMOIAssociated Cancers / Distinctive Features
High-penetrance (high-risk) breast cancer susceptibility genes
BRCA1
BRCA2 		BRCA1- & BRCA2-associated hereditary breast & ovarian cancer AD
  • Breast & ovarian cancer, predominantly young onset
  • Assoc w/triple-negative breast cancer (BRCA1)
CDH1 CDH1-related diffuse gastric and lobular breast cancer syndromeAD
  • Breast cancer (lobular)
  • Diffuse gastric cancer
PALB2 PALB2-related cancer susceptibility (OMIM 620442)AD
  • High-penetrance breast cancer 1
  • Ovarian cancer
  • Male breast cancer
  • Pancreatic cancer
PTEN PTEN hamartoma tumor syndrome AD
  • Breast cancer
  • Other cancers: thyroid, renal cell carcinoma, endometrial, colorectal
  • Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules
  • Affected persons usually present by late 20s.
STK11 Peutz-Jeghers syndrome AD
  • Breast cancer
  • Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular
  • GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers.
TP53 Li-Fraumeni syndrome AD
  • Breast cancer (often premenopausal)
  • Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias
  • Early onset & multiple primary cancers
Moderate-penetrance (moderate-risk) breast cancer susceptibility genes
BARD1 BARD1-related cancer susceptibility (OMIM 114480)ADBreast cancer
CHEK2 CHEK2-related cancer predisposition AD
  • Breast cancer
  • Family history of prostate cancer
RAD51C RAD51C-related cancer susceptibility (OMIM 613399)ADOvarian cancer w/moderate-penetrance breast cancer (particularly ER- & PR-negative breast cancer)
RAD51D RAD51D-related cancer susceptibility (OMIM 614291)ADOvarian cancer w/moderate-penetrance breast cancer (particularly ER- & PR-negative breast cancer)
Prostate cancer susceptibility genes
BRCA1
BRCA2 		BRCA1- & BRCA2-associated hereditary breast & ovarian cancer AD
  • Young-onset, aggressive prostate cancer
  • Family history of breast & ovarian cancer
CHEK2 CHEK2-related cancer predisposition AD~2x increased risk of prostate cancer
HOXB13 HOXB13-related cancer susceptibility (OMIM 610997)ADYoung-onset, familial prostate cancer
MLH1
MSH2
MSH6
PMS2
EPCAM 		Lynch syndrome AD
  • Colorectal cancer
  • Endometrial cancer in women
  • Gastric cancer
  • Small bowel cancer
  • Urinary tract cancers

AD = autosomal dominant; ER = estrogen receptor; GI = gastrointestinal; MOI = mode of inheritance; PR = progesterone receptor; SCTAT = sex cord tumor with annular tubules

1.

Management

Clinical management recommendations for ATM-related cancer predisposition were published by an international working group [Pal et al 2025]. When possible, recommendations should be guided by personalized risk estimates, particularly with respect to recommendations for breast surveillance and in accordance with country-specific guidelines.

Evaluations Following Initial Diagnosis

Individuals who have a germline pathogenic variant in ATM are counseled at the time of disclosure of molecular genetic test results about their options for surveillance and cancer risk reduction (see Prevention of Manifestations).

Treatment of Manifestations

At present there is insufficient evidence to recommend specific cancer management based on identification of ATM-related cancer predisposition. When indicated, radiotherapy be used in individuals with ATM-related cancer predisposition. The literature does not support avoidance of radiotherapy or dose modification based on identification of a heterozygous germline ATM pathogenic variant [Pal et al 2025].

Poly-adenosine diphosphate ribose polymerase inhibitors (PARPi) olaparib and talazoparib, in combination with enzalutamide, received FDA approval for treatment of individuals with metastatic castration-resistant prostate cancer associated with a germline pathogenic variant in one of 12 homologous recombination repair genes, including ATM. The data that led to FDA approval were predominantly based on BRCA2-related prostate cancer. ATM-related cancers show lower homologous recombination deficiency scores and there is limited evidence of efficacy in ATM-related cancer predisposition [Pal et al 2025].

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields.

Prevention of Manifestations

Women with ATM-related cancer predisposition do not usually meet the risk threshold to offer bilateral risk-reducing mastectomy; however, most international guidelines are supportive of considering bilateral risk-reducing mastectomy in the context of a personalized risk assessment including family history, mammographic density, hormonal risk factors, and polygenic score where available using a shared decision-making approach with the affected individual [Pal et al 2025] (see also NCCN Guidelines, Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate Version 3.2026 [login required; accessed 6-2-26]).

Women with ATM-related cancer predisposition do not usually meet the risk threshold to offer risk-reducing bilateral salpingo-oophorectomy. This threshold varies between countries, with the United Kingdom recommending consideration of surgery at a 5% lifetime risk of ovarian cancer and United States guidelines proposing a lower threshold of 3%-4% lifetime risk [Liu et al 2022] (see also NCCN Guidelines, Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate Version 3.2026 [login required; accessed 6-2-26] and NICE Guidance, Ovarian Cancer: Identifying and Managing Familial and Genetic Risk). However, bilateral salpingo-oophorectomy should be considered in women with a family history of ovarian cancer, or if gynecologic surgery is planned for other reasons using a shared decision-making approach with the affected individual [Pal et al 2025].

There is currently no specific evidence about risk-reducing therapies (chemoprevention) in women with ATM-related cancer predisposition. Endocrine risk-reducing therapies (e.g., tamoxifen, raloxifene, or anastrozole) can be considered in the context of family history and personalized risk estimates; they may be more beneficial in this group given the preponderance of estrogen receptor (ER)–positive breast cancers.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 4 are recommended.

Table 4.

ATM-Related Cancer Predisposition: Recommended Surveillance

System/ConcernEvaluationFrequency
Breast cancer
(females)		Breast self-exam trainingAt time of identification of ATM pathogenic variant
MammogramAnnually beginning at age 40 yrs
Breast MRI
  • Annually beginning at age 30-35 yrs depending on location-specific guidelines
  • US: Consider annually beginning at age 30-35 yrs. 1
  • UK: Consider annually beginning at age 30 yrs based on individual risk assessment w/CanRisk demonstrating lifetime breast cancer risk ≥40% 2 in conjunction w/specific 10-yr age-related risks. 3
  • UK: Those w/ATM pathogenic variant c.7271T>G should be managed using "Very High Risk Screening" guidelines w/annual MRI from age 30-50 yrs. 3
  • Spain: Consider annually beginning at age 40 yrs. 4
Prostate cancer
(males)		Serum PSA (± digital rectal exam)
  • US: Annually beginning at age 40 yrs
  • UK: Consider based on family history.
Pancreatic cancer Contrast-enhanced MR cholangiopancreatography or endoscopic ultrasound, in facility w/experience in screening high-risk persons for pancreatic cancer
  • US: Annually beginning at age 50 yrs or 10 yrs earlier than youngest diagnosis of exocrine pancreatic cancer in family. 1
  • UK: No surveillance recommended; those w/family history of pancreatic cancer are eligible for surveillance through research study.
  • Spain: Consider in ATM heterozygotes w/1st-degree relative w/pancreatic cancer from age 50 yrs or 10 yrs before youngest diagnosis in family. 4
Other cancers To date, there are no recommendations for enhanced surveillance for other cancers.

PSA = prostate-specific antigen; UK = United Kingdom; US = United States

1.
2.

Although ATM-related cancer predisposition is typically associated with moderate or intermediate breast cancer risk, the risk can be influenced by the ATM variant type, family history, hormonal and lifestyle factors, and non-ATM genetic risk factors. There is very limited evidence about hormonal and lifestyle factors that is specific to ATM heterozygotes, but the breast cancer risk is likely to be modified by hormonal factors (age at menarche, parity, age at first birth, use of oral contraception, use of hormone replacement therapy) and alcohol.

3.
4.

Agents/Circumstances to Avoid

Effects of therapeutic radiation doses have been studied in individuals with ATM-related cancer predisposition. Individuals with ataxia-telangiectasia (i.e., biallelic ATM pathogenic variants) are known to have extreme radiation sensitivity. This is not the case for ATM heterozygotes; women with breast cancer and a heterozygous ATM pathogenic variant did not have an increased risk for development of acute or late toxicity after breast radiation [Bremer et al 2003]. Moreover, there is no evidence for an increased risk of a second primary malignancy after adjuvant radiotherapy for breast cancer in women with ATM-related cancer predisposition [Pal et al 2025].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic male and female at-risk relatives of an individual with ATM-related cancer predisposition in order to identify family members who may benefit from appropriate surveillance and early diagnosis and treatment of ATM-related cancer.

In general, molecular genetic testing for ATM-related cancer predisposition is not recommended for at-risk individuals younger than age 18 years. However, if both parents of an individual younger than age 18 years have ATM pathogenic variants and, consequently, the individual is at risk of inheriting biallelic ATM pathogenic variants and being affected with ataxia-telangiectasia, genetic testing should be offered because it will affect medical management in childhood.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A number of ongoing studies are investigating novel approaches to the treatment of ATM-associated breast and prostate cancer. The majority of these studies involve PARPi. However, to date, there is insufficient evidence to recommend specific cancer treatments based on identification of ATM-related cancer predisposition [Pal et al 2025].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

ATM-related cancer predisposition is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • The vast majority of individuals with a germline ATM pathogenic variant inherited the pathogenic variant from a parent. The parent with the pathogenic variant may or may not have had a cancer diagnosis depending on the following variables:
    • Penetrance of the variant
    • Sex of the parent
    • Age of the parent
    • Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
    • Early death of the parent
  • A small proportion of individuals diagnosed with ATM-related cancer predisposition may have the disorder as the result of a de novo pathogenic variant; however, the proportion of probands who have a de novo pathogenic variant is unknown.
  • It is appropriate to offer molecular genetic testing to both parents of an individual with ATM-related cancer predisposition to determine which side of the family is at risk and to assess their need for ATM-related cancer surveillance.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • De novo occurrence of an ATM pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the ATM pathogenic variant.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If one parent of the proband is known to have a germline ATM pathogenic variant, the risk that a sib will inherit the pathogenic variant and have ATM-related cancer predisposition is 50%. The risk of developing cancer in a sib who inherits the familial ATM pathogenic variant depends on numerous variables including the penetrance of the pathogenic variant and the sex and age of the heterozygous sib.
  • If both parents of the proband are heterozygous for a germline ATM pathogenic variant, sibs of the proband have a 25% chance of inheriting biallelic ATM pathogenic variants and having ataxia-telangiectasia, a 50% chance of inheriting one pathogenic variant and having ATM-related cancer predisposition, and a 25% chance of inheriting neither of the familial pathogenic variants.

Offspring of a proband

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the ATM pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing for at-risk asymptomatic family members requires prior identification of the germline ATM pathogenic variant in the family.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

At-risk asymptomatic adult relatives. In general, relatives of an individual who has a germline ATM pathogenic variant should be counseled regarding their risk of having inherited the same pathogenic variant, their options for molecular genetic testing, their cancer risk, and recommendations for cancer screening (see Surveillance).

At-risk adult relatives who have not inherited the cancer-predisposing germline ATM variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on personal risk factors and their family history.

For family members determined to be at general population risk of developing cancer, appropriate cancer screening such as that recommended by the American Cancer Society or the National Comprehensive Cancer Network (NCCN) for individuals of average risk is recommended.

Testing of asymptomatic individuals younger than age 18 years. In general, genetic testing for ATM-related cancer predisposition is not recommended for at-risk individuals younger than age 18 years. The autonomy of the minor is a primary concern and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making. Because recommended surveillance for ATM-related cancer typically begins at age 30-40 (depending on local/national guidelines), genetic testing can be deferred until an individual reaches adulthood. However, if both parents of an individual younger than age 18 years have ATM pathogenic variants and, consequently, the individual is at risk of inheriting biallelic ATM pathogenic variants and being affected with ataxia-telangiectasia, genetic testing should be offered because it will affect medical management in childhood.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a germline ATM pathogenic variant or are at risk of having a germline ATM pathogenic variant.
  • ATM genetic testing should be considered for the reproductive partners of individuals with ATM-related cancer predisposition to determine if offspring are at risk of inheriting biallelic pathogenic variants and having ataxia-telangiectasia. Increased heterozygote frequencies have been reported in several populations (see Ataxia-Telangiectasia, Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

Once the ATM pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Cancer Society
    Phone: 800-227-2345
  • Cancer Nation
    Phone: 877-NCCS-YES
    Email: info@canceradvocacy.org
  • CancerCare
    Phone: 800-813-4673
    Email: info@cancercare.org
  • FORCE
    A discussion forum specifically for women who are at a high risk of developing ovarian cancer or breast cancer
    Facing Hereditary Cancer Empowered
    Phone: 866-288-7475
    Email: info@facingourrisk.org
  • National Breast Cancer Coalition (NBCC)
    Phone: 800-622-2838; 202-296-7477
    Email: info@stopbreastcancer.org
  • National Cancer Institute (NCI)
    Phone: 800-422-6237
    Email: NCIinfo@nih.gov
  • National Cancer Institute (NCI)
    Phone: 800-422-6237
  • National Cancer Institute (NCI)
    Phone: 800-4-CANCER
    Email: NCIinfo@nih.gov
  • National Ovarian Cancer Coalition
    Phone: 888-682-7426; 214-273-4200
    Email: nocc@ovarian.org
  • Sharsheret
    Phone: 866-474-2774
    Email: info@sharsheret.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

ATM-Related Cancer Predisposition: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ATM11q22​.3Serine-protein kinase ATMAtaxia Telangiectasia Mutated (ATM) @ LOVDATMATM

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for ATM-Related Cancer Predisposition (View All in OMIM)

114480BREAST CANCER
607585ATM SERINE/THREONINE KINASE; ATM

Molecular Pathogenesis

ATM encodes a serine/threonine kinase, serine-protein kinase ATM, which belongs to the phosphatidylinositol 3-kinase family of proteins. ATM is the master regulator of cellular responses to double-stranded DNA breaks. In response to double-stranded DNA breaks (e.g., on exposure to ionizing radiation), ATM phosphorylates hundreds of proteins involved in DNA repair, cell cycle checkpoints, and apoptosis, including P53, CHK2, and BRCA1 [Blackford and Jackson 2017].

Mechanism of disease causation. Loss of function

ATM-specific laboratory technical considerations. Specifications of the American College of Medical Genetics and Genomics / Association for Molecular Pathology variant curation guidelines for the analysis of germline ATM sequence variants were published in 2024 [Richardson et al 2024] by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel. Updated ATM variant interpretation guidelines were released 7-14-2025 (see ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.4.0).

There is uncertainty about the clinical utility of reporting ATM missense variants, apart from c.7271T>G, due to the lower odds ratios reported for breast cancer risk. The Evidence-Based Network for Interpretation of Germline Mutant Alleles (ENIGMA) group suggested reporting germline cancer susceptibility variants only if there is a twofold or higher risk [Spurdle et al 2019]. The UK Cancer Genetics Group statement of reporting practice for variants in ATM v2.2 recommends that for diagnostic testing (cancer indications) National Health Service laboratory teams should restrict their interpretation and reporting to canonical protein truncating variants and c.7271T>G. This is partly due to resource considerations.

Table 5.

ATM Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_000051​.4
NP_000042​.3 		c.103C>Tp.Arg35TerRecurrent pathogenic variant identified in persons of Sephardic Jewish ancestry from Morocco & Tunisia [Gilad et al 1996]
c.1564_1565delGAp.Glu522IlefsTer43Recurrent pathogenic variant identified in Amish community [Telatar et al 1998]
c.5908C>Tp.Gln1970TerRecurrent pathogenic variants identified in persons of Costa Rican ancestry [Telatar et al 1998]
c.7449G>Ap.Trp2483Ter
c.4507C>Tp.Gln1503Ter
c.6200C>Ap.Ala2067AspRecurrent pathogenic variant identified in Canadian Mennonite community [Nakamura et al 2014]
c.7271T>Gp.Val2424GlyRecurrent pathogenic variant identified in persons from British Isles & other populations, assoc w/higher breast cancer risk [Goldgar et al 2011]
c.7570G>Cp.Ala2524ProRecurrent pathogenic variant identified in Finnish persons, assoc w/higher breast cancer risk [Kankuri-Tammilehto et al 2023]
c.9007_9034del28p.Asn3003AspfsTer6Recurrent pathogenic variant identified in persons of Romani ancestry from Spain [Carranza et al 2017]
c.1339C>Tp.Arg447TerRecurrent pathogenic variant identified in persons of Druze ancestry [Avnat et al [2023]
NM_000051​.4 c.1803-270T>G--Deep intronic pathogenic variant that affects splicing [Maroilley et al 2022]
c.2639-384A>G--Deep intronic pathogenic variant that affects splicing [Nakamura et al 2012]
c.2839-579_2839-576delAAGT--Deep intronic pathogenic variant that affects splicing [Pagani et al 2002]
c.3994-159A>G--Deep intronic pathogenic variant that affects splicing [Coutinho et al 2005]
c.5763-1050A>G
(5762ins137)		--Recurrent pathogenic variant identified in persons from British Isles; deep intronic variant that affects splicing [McConville et al 1996]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Revision History

  • 4 June 2026 (sw) Review posted live
  • 5 March 2026 (krs) Original submission

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