Photo Credit: iStock.com/Nattakorn

The following is a summary of “Association of Gene Variant Type and Location with Breast Cancer Risk in the General Population,” published in the April 2025 issue of the Annals of Oncology by Akamandisa et al.

Pathogenic variants (PVs) in genes such as ATM, BRCA1, BRCA2, CHEK2, and PALB2 are known to increase breast cancer risk, but it remains unclear whether specific PV types or their locations within these genes influence the magnitude of risk, particularly among women identified through population-based screening. This study aimed to assess breast cancer risk associated with the type and location of PVs within these genes using a large, population-based cohort.

Researchers conducted an age-adjusted, case-control association analysis utilizing data from 32,247 women diagnosed with breast cancer and 32,544 age-matched controls without breast cancer from the CARRIERS Consortium. Variants were categorized based on their type and specific gene location, and logistic regression models were used to estimate ORs, 95% CIs, and corresponding p-values for breast cancer risk.

The results revealed significant heterogeneity in breast cancer risk based on the location of PTVs within BRCA2. Compared to women harboring BRCA2 PTVs located in exon 11, those with PTVs in exons 1–10 demonstrated a substantially higher risk (OR = 13.5, 95% CI: 6.0–38.7, P < 0.001), as did those with PTVs in exons 13–27 (OR = 9.0, 95% CI: 4.9–18.5, P < 0.001). 

Additionally, PTVs located in exons 1–10 and 13–27 were associated with a lower likelihood of ER-negative breast cancer (ex13–27 OR = 0.5, 95% CI: 0.2–0.9, P = 0.035; ex1–10 OR = 0.5, 95% CI: 0.1–1.0, P = 0.065) and an earlier age at diagnosis (ex13–27: 5.5 years earlier, P < 0.001; ex1–10: 2.4 years earlier, P = 0.169). These findings were independently validated in two additional cohorts: a high-risk clinical cohort from Ambry Genetics and the population-based UK Biobank cohort. No significant differences in breast cancer risk were observed by gene region for PTVs in ATM, BRCA1, CHEK2, or PALB2.

In conclusion, these findings establish that the location of PTVs within BRCA2 significantly modifies breast cancer risk, influencing both the likelihood of ER-negative disease and age at diagnosis. Notably, PTVs in exon 11 are associated with a comparatively lower risk and later disease onset. Recognizing these differential risks may enhance individualized breast cancer risk prediction and guide clinical management strategies for women carrying BRCA2 PTVs.

Source: annalsofoncology.org/article/S0923-7534(25)00170-X/fulltext