What type of study is this?

This is a Validation Study study.

What question did this study set out to answer?

This research aims to validate the association between the CHEK2 c.1100delC variant and timing of natural menopause.

February 16, 2026Journal of Medical Genetics0 citationsOpen Access

Later age of natural menopause among women with the pathogenic CHEK2 c.1100delC variant: a validation study

MSMaartje A. C. SchreursErasmus MC Cancer Institute AHAntoinette HollestelleErasmus MC Cancer Institute MAMuriel A Adank

Key Points

This research aims to validate the association between the CHEK2 c.1100delC variant and timing of natural menopause.
Genetic testing was conducted for women in the HEreditary Breast and Ovarian cancer Netherlands study.
Participants completed a questionnaire regarding reproductive and lifestyle risk factors.
ANM comparisons were made between CHEK2 c.1100delC carriers and non-carrier relatives with Cox regression models used for analysis.
CHEK2 c.1100delC women reached ANM at 51.8 years, significantly later than non-carrier relatives (50.3 years) and unrelated non-carriers (49.6 years).
Cox regression indicated a higher hazard ratio (HR 1.58) for later ANM in carriers compared to unrelated non-carriers, and an HR of 1.83 compared to non-carrier relatives.

Abstract

Background The average age of natural menopause (ANM) for European women is 50–52 years. Reproductive risk and lifestyle factors have been found to be associated with ANM. Furthermore, a genome-wide association study found that women with a CHEK2 variant reach ANM 3.49 years later than women without a CHEK2 variant (‘non-carriers’). With this study, we aim to validate this association within CHEK2 c.1100delC families. Methods As part of the HEreditary Breast and Ovarian cancer Netherlands (Hebon) study, all women who underwent genetic testing for pathogenic variants associated with breast or ovarian cancer were invited to participate and complete a questionnaire on established risk factors. We compared the reported ANM between groups and within selected birth cohorts. HRs and 95% CIs for the association of CHEK2 status with ANM were estimated via Cox regression models, adjusted for age of menarche, parity, smoking status and hormonal contraceptive use. Results We included 661 CHEK2 c.1100delC heterozygotes, 175 non-carrier relatives and 8839 unrelated non-carriers. CHEK2 c.1100delC women reached ANM at a significantly later age (51.8±4.8 years) compared with non-carrier relatives (50.3±4.0 years) and unrelated non-carriers (49.6±4.8 years). Similar patterns were found within the birth cohorts. In Cox regression analysis, heterozygotes were associated with a later ANM compared with unrelated non-carriers (HR 1.58; 95% CI 1.21 to 2.08) and non-carrier relatives (HR 1.83; 95% CI 1.13 to 2.95). Conclusion CHEK2 c.1100delC is associated with 1.5–2.2 years later ANM compared with non-carriers, underlining the independence of CHEK2 c.1100delC irrespective of heritability of ANM within families.

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