Clinical characteristics.

CHEK2-related cancer predisposition is predominantly characterized by an increased risk of female breast cancer. To a lesser extent there is an association with increased risk of prostate cancer. Associations for other cancers are less well established or conflicting. Cancer risks in those with CHEK2-related cancer predisposition can vary considerably depending on modifying factors such as family history.

Diagnosis/testing.

The diagnosis of CHEK2-related cancer predisposition is established in a proband with a heterozygous germline pathogenic variant in CHEK2 identified by molecular genetic testing.

Management.

Treatment of manifestations: Standard cancer treatments are recommended. Breast cancer risk-reducing contralateral mastectomy is generally not recommended but may be considered in some situations.

Surveillance: Breast cancer surveillance in females typically includes breast self-exam training and symptom awareness; mammogram every 12 months beginning at age 40 years; breast MRI recommendations vary by location. Prostate cancer surveillance in males includes serum PSA to be considered annually beginning at age 40 years especially in those with a strong family history of prostate cancer.

Evaluation of relatives at risk: Molecular genetic testing of at-risk female and male adult relatives can identify those family members who also have the familial pathogenic variant and thus may benefit from increased cancer surveillance.

Genetic counseling.

CHEK2-related cancer predisposition is an autosomal dominant disorder (i.e., individuals who have one copy of a CHEK2 pathogenic variant have the disorder). Most individuals with CHEK2-related cancer predisposition have a heterozygous pathogenic variant. Rarely, affected individuals have biallelic pathogenic variants. The vast majority of individuals with a heterozygous germline CHEK2 pathogenic variant inherited the pathogenic variant from a parent who may or may not have had a cancer diagnosis. The offspring of an individual identified as having a heterozygous germline CHEK2 pathogenic variant have a 50% chance of inheriting the pathogenic variant. All offspring of an individual identified as having biallelic germline CHEK2 pathogenic variants will inherit a pathogenic variant. Once the CHEK2 pathogenic variant(s) have been identified in an affected family member, predictive testing for at-risk relatives is possible.

Suggestive Findings

CHEK2-related cancer predisposition should be suspected in probands with the following clinical findings, family history, and/or laboratory findings.

Clinical findings

• Estrogen receptor (ER)-positive breast cancer, particularly young onset and/or bilateral breast cancer in a proband with a family history of breast cancer in close relatives
• Prostate cancer, particularly in a proband with a family history of prostate and/or breast cancer
• Results from a risk assessment model incorporating family history, personal risk factors, ER status of breast cancer, and breast cancer diagnoses in a family indicates an increased likelihood of identifying a CHEK2 pathogenic variant (e.g., CanRisk)

Family history can be consistent with autosomal dominant inheritance (e.g., affected males and females across multiple generations). However, as CHEK2 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.

Laboratory findings. Identification of a CHEK2 pathogenic variant on tumor tissue testing may indicate the presence of a germline variant. Note: In an analysis of 45,472 non-hypermutated solid malignancy tumor samples from individuals treated at a single oncology center, a high proportion of filtered CHEK2 variants (89.9%, 187/208) were of true germline origin. Variants filtered for inclusion in the overall analyses were those with (1) minor allele frequency (MAF) <1%, (2) 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].

Establishing the Diagnosis

The diagnosis of CHEK2-related cancer predisposition is established in a proband with a heterozygous germline pathogenic (or likely pathogenic) variant in CHEK2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology 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 CHEK2 variant of uncertain significance does not establish or rule out the diagnosis. (3) Some CHEK2 variants historically reported as pathogenic / likely pathogenic, in particular c.470T>C (p.Ile157Thr) and c.1283C>T (p.Ser428Phe), are now widely considered to be lower-penetrance variants that in isolation are not associated with a level of clinically actionable risk. In addition, a third variant, c.1427C>T (p.Thr476Met), has also been suggested to be associated with a smaller increased risk [Bychkovsky et al 2022] (see Genotype-Phenotype Correlations). Guidelines from the 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]. (4) Identification of low-level mosaicism for a CHEK2 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]. 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 use of a multigene panel or single-gene testing.

• A breast cancer or multicancer multigene panel that includes CHEK2 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.
• Single-gene testing. Sequence analysis of CHEK2 can 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.

Clinical Description

CHEK2-related cancer predisposition is predominantly characterized by an increased risk of female breast cancer [Dorling et al 2021, Hu et al 2021] and contralateral breast cancer [Morra et al 2023, Yadav et al 2023]. To a lesser extent there is an association with prostate cancer [Dong et al 2003, Pritchard et al 2016]. Associations for other cancers are less well established or conflicting. Notably, cancer risks can vary considerably depending on modifying factors such as family history. The following description of the phenotypic features associated with this condition is based on these reports.

Breast cancer. Large case-control studies have reported an increased risk of breast cancer for females heterozygous for the germline CHEK2 pathogenic variant c.1100delC (p.Thr367MetfsTer15), with an odds ratio (OR) of 2.66 (95% confidence interval [CI]: 2.27-3.11). An OR of 2.13 (95% CI: 1.60-2.84) is reported for other CHEK2 truncating pathogenic variants, and an OR of 2.47 (95% CI: 2.02-3.05) is reported for all individuals combined with a germline CHEK2 pathogenic variant [Dorling et al 2021, Hu et al 2021].

The magnitude of increased risk of breast cancer in CHEK2 heterozygotes is highest in females under age 40 years (OR = 4.54, 95% CI: 2.87-7.17) compared to females older than age 60 years (OR = 2.22, 95% CI: 1.72-2.86) [Dorling et al 2021].

Similar to breast cancers occurring in the general population, breast cancers occurring in CHEK2 heterozygotes are more likely to be estrogen receptor (ER) positive than ER negative or triple-negative subtypes [Dorling et al 2021, Hu et al 2021]. An association with human epidermal growth factor receptor 2 (HER2)-positive breast cancers has also been suggested by some studies [Agaoglu et al 2024, de Baumont et al 2024]. Unlike breast cancers associated with other breast cancer predisposition genes, breast cancers occurring in CHEK2 heterozygotes do not typically display genomic features of homologous recombination repair deficiency (HRD).

There have been mixed reports about the impact of CHEK2 status on cancer outcomes. Some studies have not demonstrated any difference in outcomes for individuals with CHEK2-related cancer predisposition [Kilpivaara et al 2005, Huzarski et al 2014], while some studies have demonstrated significantly adverse outcomes (measured as overall survival [OS], breast cancer-specific survival, and incidence of contralateral breast cancer) for CHEK2 c.1100delC (p.Thr367MetfsTer15) heterozygotes, with or without the administration of adjuvant chemotherapy and/or hormone therapy [de Bock et al 2004, Meyer et al 2007, Schmidt et al 2007, Weischer et al 2012]. A study specifically focused on 2,344 individuals diagnosed with breast cancer under age 40 years, including 53 CHEK2 heterozygotes, reported that overall survival and distant disease-free survival were significantly worse in CHEK2 heterozygotes compared to individuals without a CHEK2 pathogenic variant, even when adjusted for other known prognostic factors (OS hazard ratio [HR] = 1.58, 95% CI: 1.01-2.48, P=0.043) [Greville-Heygate et al 2020]. Given that most cancers in CHEK2 heterozygotes are ER-positive cancers, generally associated with more favorable outcomes, these observations need additional studies to investigate these findings further.

Contralateral breast cancer (CBC). An increased risk of CBC has been reported in CHEK2 heterozygotes. Two large studies, Breast Cancer Association Consortium's (BCAC) Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES) and Cancer Risk Estimates Related to Susceptibility (CARRIERS), demonstrated similar risks: HR = 2.25 (95% CI: 1.55-3.27) and HR = 2.0 (95% CI: 1.0-4.2), respectively [Morra et al 2023, Yadav et al 2023]. In the CARRIERS study, the risk of CBC was reported to be greatest among females whose initial breast cancer occurred at a young age. Among premenopausal females, the ten-year cumulative incidence of CBC was estimated to be 13%, compared to postmenopausal females, who were found to have a ten-year cumulative incidence of CBC of 4%.

Radiotherapy has not been demonstrated to impact CBC risk for CHEK2 heterozygotes in a small number of studies undertaken to date [Reiner et al 2020].

Male breast cancer. An increased risk of male breast cancer has been reported in CHEK2 heterozygotes, although published studies have been limited to small single-country studies and predominantly focused on c.1100delC (p.Thr367MetfsTer15) heterozygotes [Hallamies et al 2017, Schreurs et al 2024]. A metanalysis including 26 studies reported an increased risk of male breast cancer for CHEK2 heterozygotes (OR = 3.13, 95% CI: 1.94-5.07) [Liang et al 2018]. CHEK2 heterozygotes developed male breast cancer at younger ages than sporadic male breast cancer or male breast cancer due to pathogenic variants in other genes [Pritzlaff et al 2017]. No clear histopathologic associations have been described for breast cancers occurring in male CHEK2 heterozygotes.

Prostate cancer. CHEK2 pathogenic variants are associated with approximately twofold increased risk of prostate cancer; cumulative lifetime risk figures have not been published. Studies have identified a higher prevalence of germline CHEK2 pathogenic variants in males with metastatic prostate cancer, suggesting that CHEK2 heterozygosity is associated with more aggressive disease [Pritchard et al 2016, Wu et al 2018].

Other cancers with unconfirmed association with CHEK2 pathogenic variants. CHEK2 has been proposed to be associated with many cancers and to potentially act as a low-to-moderate-risk multitumor predisposition gene. Other cancers, particularly colorectal, renal, and papillary thyroid cancer, as well as many others such as sarcoma, pancreatic, stomach, melanoma, endometrial, bladder, testicular, and hematologic malignancies have been suggested to be increased in CHEK2 heterozygotes, but further data are required to confirm any clear associations with clinically actionable risks [Hanson et al 2023]. Note: Early studies suggested that variants in CHEK2 were associated with Li-Fraumeni syndrome. However, subsequent studies firmly refuted this, and it is now widely acknowledged that variants in CHEK2 do not cause Li-Fraumeni syndrome.

• Colorectal cancer (CRC). Studies on the association of CHEK2 with CRC have been conflicting. A study focusing on CHEK2 pathogenic variant c.1100delC (p.Thr367MetfsTer15) in a Dutch population found an increased CRC risk in heterozygotes compared to the general population from age 45 in females and age 55 in males, with an overall standardized incidence ratio (SIR) of 1.43 (95% CI: 1.14-1.76, absolute excess risk = 1.4); SIR was 3.44 in individuals age 45-50 years [Schreurs et al 2024]. In comparison, a retrospective cohort study of individuals with cancer or family history of cancer who had multigene panel testing did not find an association between CHEK2 and CRC. In fact, individuals with a CHEK2 pathogenic variant (n=3,783) had fewer instances of CRC, compared with individuals without a CHEK2 germline pathogenic variant (n=33,034) (OR = 0.62, 95% CI: 0.51-0.76, P <0.001) [Bychkovsky et al 2022]. A further commercial laboratory-based study also did not find an association of either truncating or missense CHEK2 variants with CRC risk in more than 6,000 heterozygotes (OR = 1.10, 95% CI: 0.91-1.33, P=0.30600). Consequently, there is insufficient data to support a clinically meaningful increased risk of CRC among CHEK2 heterozygotes. Further research is needed to determine if enhanced surveillance is of benefit to specific CHEK2 heterozygotes.
• Thyroid cancer. An increased risk of papillary thyroid cancer has been suggested in CHEK2 heterozygotes. However, studies reporting a statistically significant increased risk are limited to a single country or specific variant (e.g., the Polish founder variant c.444+1G>A) [Siołek et al 2015]. In fact, studies from other countries have not identified statistically increased risks or have reported lower risks (OR <2) [Näslund-Koch et al 2016, Bychkovsky et al 2022, Brock et al 2024].
• Renal cancer. Studies of an association of CHEK2 with renal cancer have also been conflicting. Some studies have reported an association [Carlo et al 2018, Hartman et al 2020, Bychkovsky et al 2022], whereas others have not [Näslund-Koch et al 2016, Schreurs et al 2024]. In a large series of unselected individuals with renal cell cancer (n=1336) and controls (n=5834) recruited to the UK 100,000 Genomes Project, whole-genome sequencing data demonstrated a significant excess of CHEK2 variants in individuals with renal cancer compared to controls (P=0.0019); the mean age of individuals was reported to be 65.5 years, suggesting a potential age-related association, but overall lifetime cancer risk was not studied [Yngvadottir et al 2022]. Although current studies are largely supportive of a possible increased risk of renal cancer, additional studies are required to confirm an association and determine if there is a predisposition for a specific histopathologic subtype to inform surveillance recommendations.

Homozygous / Compound Heterozygous Individuals

Individuals homozygous for CHEK2 c.1100delC (p.Thr367MetfsTer15) are reported to have a higher risk for both unilateral and bilateral breast cancer [Rainville et al 2020, Hinić et al 2024, Schreurs et al 2024]. In one study of individuals identified through multigene panel testing that included 6,473 CHEK2 heterozygotes and 31 individuals with biallelic CHEK2 pathogenic variants, individuals with biallelic CHEK2 pathogenic variants had a significantly higher risk for invasive breast cancer (OR = 8.69, 95% CI: 3.69-20.47), were more likely to be diagnosed at or before age 50 years, and were more likely to have multiple primary breast cancers compared to CHEK2 heterozygotes. The higher reported cancer risks were only statistically significant for breast cancer [Bychkovsky et al 2022].

A small number of case reports have described a cancer predisposition syndrome with early adult onset and/or multiple primary cancers with somatic chromosome instability and multiple cytogenetic abnormalities identified in tumor tissue in individuals with CHEK2 biallelic pathogenic variants. One report described two unrelated individuals homozygous for c.499G>A (p.Gly167Arg), one with multiple primary tumors and one with early-onset leukemia [Paperna et al 2020]. Another reported an individual homozygous for c.793-1G>A and an individual compound heterozygous for c.1100delC (p.Thr367MetfsTer15) and c.1312G>T (p.Asp438Tyr), both with multiple primary tumors [Bottillo et al 2023].

The largest study of individuals with biallelic CHEK2 pathogenic variants ascertained via the ERN GENTURIS network (n=294) confirmed an association of biallelic loss-of-function variants with early-onset breast cancer and multiple breast and other cancers [Hinić et al 2024]. More than half of females with biallelic loss-of-function CHEK2 variants developed at least two cancers, with approximately half developing cancers other than breast cancer. A higher risk of CRC when compared with monoallelic carriers was also suggested.

Genotype-Phenotype Correlations

Cancer risk estimates for CHEK2 heterozygotes with missense variants have been reported to be lower than estimates for CHEK2 truncating variants in some studies [Sutcliffe et al 2020, Dorling et al 2021, Dorling et al 2022]. A large study from BRIDGES estimated an OR <1.5 (OR = 1.42, 95% CI: 1.28-1.58, P= 2.5 × 10⁻¹¹) for rare missense variants (defined as variants with a population frequency of <0.001) and found no correlation with the variant position in the gene, while the OR for truncating variants was 2.66 (95% CI: 2.27-3.11) [Dorling et al 2021].

However, genotype-phenotype correlations have been difficult to determine due to inclusion of low-penetrance missense variants in studies of cancer risk, thus influencing the risk for missense variants as a whole. Some missense variants historically considered pathogenic are now recognized as low-penetrance variants that in isolation do not reach a level of clinical actionability. The most notable examples are c.470T>C (p.Ile157Thr) and c.1283C>T (p.Ser428Phe). In a large population-based case-control study of 32,247 women with breast cancer and 32,544 unaffected women, the OR for both these variants when separately analyzed fell below 1.5 (p.Ile157Thr: OR = 1.30, 95% CI: 1.06-1.59, P=0.01 and p.Ser428Phe: OR = 1.26, 95% CI: 0.76-2.12, P=0.37) [Hu et al 2021].

To further compare cancer risk associated with truncating versus missense variants, a commercial laboratory-based study of 6,000 CHEK2 pathogenic variants excluded both c.470T>C (p.Ile157Thr) and c.1283C>T (p.Ser428Phe) from the analysis of missense variants and reported no statistically significant differences when truncating pathogenic variants (P <0.001) and missense pathogenic variants (P <0.001) were evaluated separately [Mundt et al 2023]. Similar findings were reported in other retrospective analyses of multigene panel testing for these two variants [Bychkovsky et al 2022]. It is therefore suggested that these two variants are best considered comparable to other common breast cancer risk single-nucleotide polymorphisms within a polygenic risk score, rather than a single-gene cause [Ivanov et al 2022, Mundt et al 2023].

Penetrance

The penetrance of breast and other cancers associated with pathogenic variants in CHEK2 is typically in the range of 20%-30%, but overall individual lifetime risk can be lower or higher when modifying factors are taken into consideration. CHEK2 is considered a moderate risk or intermediate penetrance cancer predisposition gene (see Table 2 for associated cancer risks).

Genetic Modifiers

Individuals containing pathogenic variants in both CHEK2 and ATM (excluding low-risk variants) were found to be diagnosed with breast cancer at a younger age compared to those with a single pathogenic variant in either gene. This significant difference is primarily driven by the age of breast cancer onset. Additional studies are necessary to validate these findings [Agaoglu et al 2024].

A cohort study of 3,783 individuals heterozygous for pathogenic / likely pathogenic (P/LP) and low-risk CHEK2 variants demonstrated that low-risk variants such as c.470T>C (p.Ile157Thr), c.1283C>T (p.Ser428Phe), and c.1427C>T (p.Thr476Met), when found in combination with a P/LP variant, were associated with a more penetrant cancer phenotype. These included increased incidence of cancer, multiple primary cancers, and bilateral breast cancer. Further investigation of this potential modifier effect is warranted [Bychkovsky et al 2025].

Prevalence

CHEK2 pathogenic variant c.1100delC (p.Thr367MetfsTer15) is prevalent in northern European populations, with a prevalence of 1% reported in the Netherlands [Schreurs et al 2024].

The CHEK2 low-risk variants c.470T>C (p.Ile157Thr), c.1283C>T (p.Ser428Phe), and c.1427C>T (p.Thr476Met) have been observed with varying frequency across populations: 0.2% in non-Finnish Europeans, 1.1% in Ashkenazi Jewish individuals, and 0.05% in the broader European population [Bychkovsky et al 2025].

Several other CHEK2 pathogenic variants have been reported to be more common in specific populations (see Table 5).

Evaluations Following Initial Diagnosis

Individuals who have a germline pathogenic variant in CHEK2 are counseled at the time of disclosure of molecular genetic test results about their options for surveillance and prevention of primary manifestations.

Treatment of Manifestations

At present there is insufficient evidence to recommend specific cancer treatment based on identification of CHEK2-related cancer predisposition. Standard cancer treatments are recommended.

Breast cancer. In those with breast cancer, risk-reducing contralateral mastectomy is generally not recommended but may be considered in some situations. This should only be undertaken following a personalized risk assessment, utilizing a model such as CanRisk that incorporates personal and family risk factors and considers remaining lifetime contralateral breast cancer (CBC) risk, alongside factors not assessed by CanRisk such as competing risk from the primary breast cancer diagnosis and potential risk reduction from endocrine treatment, given that the majority of breast cancers in individuals with a heterozygous CHEK2 pathogenic variant are estrogen receptor (ER) positive.

Prevention of Primary Manifestations

To date there are no available data on the benefit of bilateral risk-reducing mastectomy for individuals with a heterozygous CHEK2 pathogenic variant. Most international guidelines are supportive of considering this surgery in the context of a personalized risk assessment including family history using a shared decision-making approach with the affected individual [Hanson et al 2023, National Comprehensive Cancer Network 2025].

Surveillance

To monitor existing manifestations and the emergence of new manifestations, the evaluations summarized in Table 4 are recommended for all individuals with a heterozygous CHEK2 pathogenic variant.

Evaluation of Relatives at Risk

Once a cancer-predisposing CHEK2 germline pathogenic variant has been identified in a family, molecular genetic testing of at-risk female and male adult relatives can identify those family members who also have the familial pathogenic variant and thus may benefit from increased cancer surveillance as specified in Table 4.

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 CHEK2-associated breast and prostate cancer. The majority of these studies involve poly [ADP-ribose] polymerase (PARP) inhibitors. However, to date there is insufficient evidence to recommend specific cancer treatment based on identification of CHEK2-related cancer predisposition.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies.

Mode of Inheritance

CHEK2-related cancer predisposition is an autosomal dominant disorder (i.e., individuals who have one copy of a CHEK2 pathogenic variant have the disorder).

Most individuals with CHEK2-related cancer predisposition have a heterozygous CHEK2 pathogenic variant. Rarely, individuals with CHEK2-related cancer predisposition have biallelic pathogenic variants (see Clinical Description, Homozygous / Compound Heterozygous Individuals).

Risk to Family Members

Parents of a proband

• The vast majority of individuals with a heterozygous germline CHEK2 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 penetrance of the pathogenic variant, modifying factors (e.g., polygenic risk score, hormonal factors, and/or lifestyle factors), sex of the parent, age of the parent, cancer risk reduction in the parent as a result of screening or prophylactic surgeries, and early death of the parent.
• It is appropriate to offer molecular genetic testing to both parents of an individual with a CHEK2 germline pathogenic variant to determine which side of the family is at risk. Generally, the pattern of cancers seen in the family guides which parent is tested first. Note: If an individual with CHEK2-related cancer predisposition has biallelic germline pathogenic variants, it is likely that both parents are heterozygous for a CHEK2 pathogenic variant.
• 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:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.
    Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the CHEK2 pathogenic variant identified in the proband.

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 has the germline CHEK2 pathogenic variant identified in the proband, the risk that a sib will inherit the pathogenic variant is 50%. The risk of developing cancer in a sib who inherits the familial CHEK2 pathogenic variant depends on numerous variables including sex of the sib, penetrance of the pathogenic variant, modifying factors including but not limited to hormonal and/or lifestyle factors, mammographic density, and polygenic risk score (see Genotype-Phenotype Correlations).
• If both parents of the proband are heterozygous for a CHEK2 pathogenic variant, the risk that a sib will inherit at least one CHEK2 pathogenic variant is 75% (see Clinical Description, Homozygous / Compound Heterozygous Individuals).

Offspring of a proband

• The offspring of an individual with a heterozygous germline CHEK2 pathogenic variant have a 50% chance of inheriting the pathogenic variant.
• All offspring of an individual with biallelic germline CHEK2 pathogenic variants will inherit a CHEK2 pathogenic variant.
• The risk of developing cancer in offspring who inherit the CHEK2 pathogenic variant depends on numerous variables including sex of the sib, penetrance of the pathogenic variant, modifying factors including but not limited to hormonal and/or lifestyle factors, mammographic density, and polygenic risk score (see Genotype-Phenotype Correlations).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CHEK2 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.

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 are affected or at risk.

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 CHEK2 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) and risk-reducing surgery (see Prevention of Primary Manifestations) in individuals found to have a familial germline CHEK2 pathogenic variant.
• At-risk adult relatives who have not inherited the cancer-predisposing germline pathogenic variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on extent of family history of cancer attributed to the CHEK2 pathogenic variant and/or personal risk factors. 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. Note: This presumption cannot be applied to individuals in whom a CHEK2 germline pathogenic variant was not identified unless the familial CHEK2 pathogenic variant is known (i.e., the CHEK2 pathogenic variant has been identified in an affected family member).
• Testing of asymptomatic individuals younger than age 18 years. In general, genetic testing for CHEK2 cancer susceptibility 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the CHEK2 pathogenic variant(s) have 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 decisions regarding prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions, Wafik et al [2023], and the UK Cancer Genetics Group guidance for clinical practice on prenatal testing for cancer susceptibility genes.

Molecular Pathogenesis

CHEK2 encodes a key effector protein kinase that works in cell cycle regulation through activation in response to DNA damage, specifically through its role in the ATM-CHK2-p53 DNA damage response pathway [Matsuoka et al 1998].

Mechanism of disease causation. Loss of function

CHEK2-specific laboratory technical considerations. Some CHEK2 variants initially classified as pathogenic, in particular c.470T>C (p.Ile157Thr) and c.1283C>T (p.Ser428Phe), are now widely considered to be low-penetrance (low-risk) variants that in isolation are not associated with a level of clinically actionable risk. A third variant, c.1427C>T (p.Thr476Met), has also been suggested to be associated with a lower risk [Bychkovsky et al 2022].

Identification of a CHEK2 pathogenic variant with low allele frequency (e.g., significantly less than 50%) may be indicative of mosaicism, clonal hematopoiesis of indeterminate potential (CHIP), hematologic malignancy or premalignancy, or circulating tumor cells [Slavin et al 2019, Sutcliffe et al 2022]. Individuals with constitutional or early postzygotic CHEK2 mosaicism have an increased risk of CHEK2-related cancers; individuals with CHIP do not.

Sequencing analysis of CHEK2 could be complicated by the presence of ≥5 pseudogenes, dependent upon the methodology utilized.

Acknowledgments

HH is supported by the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC).

MT is supported by the NIHR Cambridge BRC.

DRS is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, Rockville, MD.

Revision History

• 25 March 2026 (aa) Revision: edits to Hereditary Diffuse Gastric Cancer row in Differential Diagnosis
• 29 May 2025 (sw) Review posted live
• 20 November 2024 (hh) Original submission

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