Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)

Abstract

Purpose: Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited.

Methods: An international workgroup developed guidance on clinical management of CHEK2 heterozygotes informed by peer-reviewed publications from PubMed.

Results: Although CHEK2 is considered a moderate penetrance gene, cancer risks may be considered as a continuous variable, which are influenced by family history and other modifiers. Consequently, early cancer detection and prevention for CHEK2 heterozygotes should be guided by personalized risk estimates. Such estimates may result in both downgrading lifetime breast cancer risks to those similar to the general population or upgrading lifetime risk to a level at which CHEK2 heterozygotes are offered high-risk breast surveillance according to country-specific guidelines. Risk-reducing mastectomy should be guided by personalized risk estimates and shared decision making. Colorectal and prostate cancer surveillance should be considered based on assessment of family history. For CHEK2 heterozygotes who develop cancer, no specific targeted medical treatment is recommended at this time.

Conclusion: Systematic prospective data collection is needed to establish the spectrum of CHEK2-associated cancer risks and to determine yet-unanswered questions, such as the outcomes of surveillance, response to cancer treatment, and survival after cancer diagnosis.

Keywords: CHEK2; Cancer predisposition; Cancer risk; Cancer surveillance; Inherited cancer.

Figure 1. Cases illustrating CHEK2 testing in practice.

CHEK2 case #1 is a 33-year-old woman who presented to the clinic with no personal history of cancer but had a history of breast cancer on both sides of the family. She was tested through a commercial laboratory, which identified the CHEK2 p.(Ile157Thr) variant and reported it as a variant of uncertain significance. There are conflicting levels of pathogenicity on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000144596/, accessed March 2023). Discussion points are as follows. (1) this variant is reported by some diagnostic laboratories as “pathogenic (low penetrance),” “moderate risk variant,” or with a “Special Interpretation” note. In some countries, the CHEK2 p.(Ile157Thr) variant is not even reported. (2) the difference between variant pathogenicity vs disease penetrance, is reflected in the differing terminology used by the various laboratories to interpret this variant. (3) in isolation, missense variants conferring less than 2-fold RR for BC and colorectal cancer (such as p.(Ile175Thr)) are not likely to result in a change in clinical management. (4) breast cancer screening recommendations should be based primarily on country-specific guidance, family history, and other risk factors. (5) colorectal cancer screening recommendations should be based primarily on country-specific guidance, family history, and other risk factors.

Figure 2. Cases illustrating CHEK2 testing in practice.

CHEK2 case #2 is a 35-year-old female who was originally diagnosed at age 33 years with stage 2 breast cancer, at which time testing ordered by her oncologist included only BRCA1/2, with no P/LP variants identified. She was subsequently diagnosed with metastases to bone at age 35, at which time tumor testing was undertaken and identified a CHEK2 c.1100del pathogenic variant. BRCA1/2 testing was already covered through insurance, but additional germline testing for CHEK2 was declined for coverage by her insurer. The individual’s father subsequently proceeded with germline testing and was identified to have the same CHEK2 c.1100del pathogenic variant. Discussion points are as follows. (1) the patient is young for a CHEK2-related breast cancer. (2) tumor sequencing may help clarify whether a CHEK2 variant is implicated in tumorigenesis in specific cancers. (3) a known common variant, such as CHEK2 c.1100del, uncovered in tumor sequencing can be presumed to be germline but still merits confirmation.

Figure 3. Cases illustrating CHEK2 testing in practice.

CHEK2 case #3 is a 45-year-old woman who had atypical ductal hyperplasia in her left breast on a recent biopsy, which was subsequently confirmed on excisional biopsy to be low-grade DCIS. She had genetic testing because of a maternal family history of cancer. Mother had DCIS at age 67, at which time she was tested for BRCA1 and BRCA2; no P/LP variants were identified. The mother’s identical twin sister also had breast cancer at age 67 and was tested through multigene panels and was negative for any P/LP variants in CHEK2. She subsequently passed from metastatic disease. The patient was tested for inherited breast cancer because of her family history and found to have a CHEK2 likely pathogenic splice-donor variant (c.1461+1G>T) (https://www.ncbi.nlm.nih.gov/clinvar/122942210/, accessed March 2023). Discussion points are as follows. (1) CHEK2 likely pathogenic variant inherited from the side of the family without any history of breast cancer. (2) testing for her siblings, particularly her sister, would be recommended. Testing her brother, given the history of prostate cancer, may also be relevant. (3) the maternal family history of breast cancer would further increase patient’s breast cancer risk. (4) breast cancer surveillance recommendations should be guided by CanRisk assessment. (5) breast cancer risk management should be recommended based on country-specific surveillance guidelines because the definition of “high” risk varies by country. (6) in the absence of a family history of colorectal cancer, colonoscopy surveillance should be offered in accordance with population-based guidelines. DCIS, ductal cancer in situ; P/LP, pathogenic/likely pathogenic.

Figure 4. Cases illustrating CHEK2 testing in practice.

CHEK2 case #4 is a 61-year-old female with breast cancer at age 56, which was treated with bilateral mastectomy. Genetic testing identified a CHEK2 pathogenic variant c.1434del p.(Glu479fs) (https://www.ncbi.nlm.nih.gov/clinvar/RCV000458226/, accessed March 2023). A multigeneration family history of breast cancer was observed on both sides of the family; however, genetic testing was not undertaken among the extended family members, aside from the 20-year-old niece, who was found to harbor the CHEK2 pathogenic variant. Discussion points are as follows. (1) per CanRisk, the niece has a >30% lifetime risk of breast cancer (Figure 5 or output 1). Country-specific surveillance guidelines should be followed for this level of risk. (2) this risk, however, can be modified in either direction by a polygenic risk score (see Figure 5 or outputs 2 and 3). (3) the use of polygenic risk scores is not standard of care at this time (pending additional validation and research) but may be helpful in development of personalized surveillance recommendations.

Figure 5

CanRisk outputs focused on 20-year-old niece of proband, showing breast cancer risks to age 80.