INTRODUCTION — This monograph summarizes the interpretation of germline testing of the CHEK2 gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or in the clinical care of the individual who was tested. These subjects are discussed separately .
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps by the laboratory: determining the genotype and interpreting the pathogenicity of the variant(s).
Classification of variants — The classification for many variants such as those deemed "likely pathogenic" or "variants of uncertain significance" (VUS) is periodically updated as more data become available . The uncertainty reflects the available research rather than the accuracy of genotyping.
If there is concern about the classification, such as for a VUS or low-penetrance variant, obtain an updated interpretation periodically (eg, annually), when clinical management or reproductive decisions might be altered or if family members present for genetic testing. This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a specialist, clinical geneticist or genetic counselor; there is no gold standard approach. Some laboratories routinely provide updates and others provide more information only when requested. Many VUS are reclassified as benign. Likely benign and benign variants are not routinely reported.
●Genotype – Identifies the variants in the gene(s) tested. If the results were obtained by direct-to-consumer testing or a research study, testing should be repeated, possibly in conjunction with additional gene tests, in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory). This is particularly true if test results would impact clinical care of the patient and/or their relatives (eg, pathogenic variant identified in a gene with known clinical significance/potential clinical actionability; negative finding in an individual with a suspected cancer syndrome or whose family member is known to carry a pathogenic variant).
●Interpretation – Determines pathogenicity of the variant(s) identified and presents a classification of such based on standard criteria. May require updating, particularly for VUS, as new research and data are available. (See 'Variant of uncertain significance' below.)
Note that it is critical to review the test report carefully. Risk information and associated management recommendations for variants in the CHEK2 gene are dependent on the specific variant identified.
The table provides a glossary of genetic testing terms (table 3).
PATHOGENIC OR LIKELY PATHOGENIC VARIANT
Disease associations — The checkpoint kinase 2 (CHEK2) gene is associated with the DNA damage repair response Fanconi anemia (FA)-BRCA1/2 pathway. Several CHEK2 pathogenic variants have been identified, but risks may be different based on the specific variant identified.
CHEK2 is considered a moderate risk cancer gene. Transmission of the cancer risk associated with CHEK2 variants is autosomal dominant with incomplete penetrance. Heterozygosity for a pathogenic or likely pathogenic variant in CHEK2 is associated with increased lifetime risks for several cancers, but many individuals will not develop cancer. The most commonly studied variants are c.1100delC and c.Ile157Thr (c.I157T).
Protein-truncating or frameshift variants in CHEK2 are associated with an increased risk for breast cancer. The c.1100delC protein-truncating variant, predominantly seen in White Americans and Europeans of Northern or Eastern European descent, is associated with a two- to threefold increased risk of breast cancer [4-17]. The cumulative breast cancer risk in females with this variant has been reported to be approximately six percent to age 49 and 32 percent to age 80 . In general, breast cancer lifetime risks for frameshift variants in CHEK2 ranges from 15 to 40 percent and appear to be higher when an individual has a family history of breast cancer [17,19,20].
Cancer risks associated with most pathogenic missense variants in CHEK2 are unclear, but are likely lower than protein-truncating variants. For example, the c.Ile157Thr variant has been associated with only a modest increase in breast cancer risk (odds ratio [OR] 1.58, 95% CI 1.42-1.75) . In a separate report, cumulative age-specific breast cancer risks for the c.Ile157Thr variant were approximately 3 percent to age 49 and 18 percent to age 80 . (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CHEK2'.)
Cancer risks — Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for first-degree and more distant relatives (see 'Genetic testing of at-risk relatives' below). The discussion of risks is individualized based on the person's age, family history of cancer, and the specific CHEK2 variant identified. It is therefore important to read the test report carefully for information about the variant identified and the current interpretation of that variant.
Breast cancer — Pathogenic and likely pathogenic frameshift germline variants in CHEK2 confer an increased risk of breast cancer, with lifetime risks ranging from 15 to 40 percent . Although specific data are lacking on other CHEK2 pathogenic/likely pathogenic variants, we usually counsel individuals with protein-truncating mutations based on data related to the c.1100delC variant, consistent with recommendations from other experts [18,19,22].
CHEK2 heterozygotes (carriers) of the c.1100delC variant are significantly more likely to be younger at the time of breast cancer diagnosis (mean age 50 years), have a family history of breast cancer, develop estrogen receptor (ER)-positive breast cancer, and develop a second primary breast cancer [14,23]. Risk for breast cancer is also increased perhaps by as much as 10-fold in males who carry the c.1100delC variant, although the absolute risk is low .
Individuals with pathogenic missense variants may be counseled similarly to those with the c.Ile157Thr variant, or counseling may be individualized based on available data.
Other cancers — The risks for other CHEK2-associated cancers are not as well defined. However, the c.1100delC variant appears to be associated with an increased risk for colorectal cancer, particularly in the setting of a family history of colorectal cancer . For example, the cumulative risk of colorectal cancer for c.1100delC carriers to age 49 is estimated to be 0.6 percent, with a cumulative lifetime risk to age 85 of approximately 12 percent . In addition, the cumulative risk of colorectal cancer for the c.Ile157Thr variant is estimated to be 0.5 percent by age 49, with a cumulative lifetime risk to age 85 of approximately 12 percent . These CHEK2-associated risks compare with a lifetime risk in the general population of approximately 6 percent. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CHEK2'.)
Studies have also found individuals with a pathogenic variant in CHEK2 have increased risks for prostate and thyroid cancers [5,26], with some evidence suggesting increased risks for kidney, colon, and stomach cancers, as well as sarcoma [5,19], although these risks are not well established. Convincing evidence that CHEK2 pathogenic variants confer an increased risk of ovarian cancer are lacking [27,28].
Management — We generally adhere to National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction. Counseling may require additional visits or referrals . Acting upon genetic test results is rarely an emergency; the individual can be reassured that management decisions can be deferred until questions are answered.
Findings in family members (type of cancers, age of onset) may also inform recommendations about surveillance (eg, starting at an earlier age if a family member has an earlier age of onset) or risk reduction.
We consider all individuals with a pathogenic or likely pathogenic variant in CHEK2 to be at risk for CHEK2-asociated cancers, regardless of the initial reason for testing. (See 'Disease associations' above.)
Cancer screening — The following screening is appropriate for individuals who are heterozygous for a pathogenic variant in CHEK2 (CHEK2 carriers):
•For females, we typically initiate annual mammography with tomography and annual magnetic resonance imaging (MRI) with gadolinium starting at age 40 years. Examinations can be staggered so that one occurs every six months. The age to initiate breast cancer screening is modified based on family history and should begin 5 to 10 years earlier than the youngest breast cancer diagnosis in the family, but no later than age 40 years.
•Evidence is insufficient to recommend risk-reducing mastectomy in CHEK2 carriers, regardless of whether or not they have had cancer. However, female carriers, especially those with a family history of breast cancer or other risks factors (eg, atypia or a breast cancer diagnosis), can consider this option and discuss the potential benefits, risks, and limitations with their providers.
•For female carriers with a concerning family history who do not undergo risk-reducing mastectomy, chemoprevention with endocrine therapy may be an appropriate option (see "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Indications'). In particular, females with a pathogenic variant in CHEK2 are more likely to develop ER-positive breast cancer and thus may be good candidates for chemoprevention with a selective estrogen response modifier (SERM) such as tamoxifen, or if postmenopausal, with raloxifene or an aromatase inhibitor. However, data regarding efficacy specifically in CHEK2 carriers are lacking.
•The absolute risk of male breast cancer is very low. Therefore, we do not pursue screening mammography or risk-reducing mastectomy in male carriers.
●Ovarian cancer — Pathogenic variants in CHEK2 do not appear to confer an increased risk for ovarian cancer. For those with a family history of ovarian cancer, we discuss the potential risks and benefits of risk-reducing bilateral salpingo-oophorectomy. (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CHEK2' and 'Cancer risks' above.)
●Colorectal cancer — We recommend colorectal cancer screening with a colonoscopy rather than other colorectal cancer screening modalities .
•For those without a first-degree relative with colorectal cancer, colonoscopy is performed every five years, beginning at age 40.
•For those with a first-degree relative with colorectal cancer, colonoscopy is performed every five years beginning either at age 40, or 10 years prior to the age of the first-degree relative's age at colorectal cancer diagnosis.
●Other cancers — Male CHEK2 carriers should review their family history of prostate cancer and discuss prostate cancer screening options (prostate-specific antigen [PSA], digital rectal exam) with their physician to determine an appropriate surveillance regimen. These discussions could be initiated at age 40. There are no other specific recommendations for increased cancer screening in CHEK2 carriers, but as always, individualized screening may be appropriate based on the family history or other risk factors. (See "Genetic risk factors for prostate cancer", section on 'CHEK2'.)
Considerations for the family
Reproductive counseling — Reproductive counseling (ideally done prior to conception) is appropriate for individuals with a pathogenic or likely pathogenic variant in CHEK2 who are considering childbearing or may wish to have children in the future.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). Testing is also available during a pregnancy or after birth. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
Genetic testing of at-risk relatives — Individuals who test positive for a pathogenic or likely pathogenic variant should inform their relatives about the importance of genetic counseling and the option of possible testing.
●The risk of having inherited the variant is 50 percent for first-degree relatives (parents, male and female siblings, children). Other at-risk relatives may include aunts, uncles, nieces, nephews, and cousins.
●Genetic testing is generally deferred until ≥18 years of age to allow for informed consent because it is very rare for CHEK2-associated cancers to occur before adulthood. (See 'Resources' below and "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
IMPLICATIONS OF A NEGATIVE TEST — Negative testing means no pathogenic variants were identified (algorithm 1). However, such results do not necessarily mean that hereditary risk is ruled out or that cancer risks for the tested individual are not elevated.
●Once a familial CHEK2 pathogenic variant is identified and the tested individual does not have that variant, they may be reassured that they are unlikely to be at high risk for CHEK2-associated cancers, with the caveats outlined above (see 'How to read the report' above). However, it is important to assess both sides of the family history, as well as other personal cancer risk factors to provide an individualized risk assessment. As with variants in other genes in which the risk assessment is particularly dependent on family history, relatives who test negative for the familial pathogenic variant may not have cancer risks that are reduced to the level of the general population [18,31]. Thus, unlike at-risk individuals in BRCA1/2-positive kindreds who receive a "true negative" result and can usually be reassured that their breast and ovarian cancer risks are about the same as the general population [32,33], such reassurance may not always be possible when there is a CHEK2 pathogenic variant in the family.
●If a familial variant in CHEK2 is not known and results of genetic testing are negative, additional risk factors for cancer (genetic or environmental) may still be present. Depending on the extent of genetic testing performed, additional testing (eg, with a multigene panel) may be indicated. Surveillance and risk reduction recommendations are based on personal risk factors and family history. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong or suggestive family history of cancer. (See 'Locating a genetics expert' below.)
VARIANT OF UNCERTAIN SIGNIFICANCE — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).
New information may become available, and the testing laboratory or other resources should be consulted periodically for updates in the classification (eg, annually). (See 'Classification of variants' above.)
●CHEK2 associated risks:
•Cancer risks – (See "Overview of hereditary breast and ovarian cancer syndromes", section on 'CHEK2'.)
•Variant classification – (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
•Terminology – (See "Genetics: Glossary of terms".)
Locating a genetics expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
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