This study investigates the genetic links between ovarian ageing, cancer risk, and de novo mutation rates. By analyzing rare protein-coding variants in 106,973 women from the UK Biobank, the researchers identified genes with effects five times larger than those found for common variants. Key findings include: 1. **Genetic Links to Ovarian Ageing**: Rare variants in genes such as *ZNF518A*, *PNPLAS*, *PALB2*, *SAMHD1*, and *ETA1* were associated with ovarian ageing, with *ZNF518A* showing the strongest effect (5.61 years earlier menopause). These findings reinforce the link between ovarian ageing and cancer susceptibility. 2. **Cancer Risk**: Damaging germline variants in *SAMHD1* were associated with increased all-cause cancer risk in both men and women, particularly for prostate cancer in men and hormone-sensitive cancers in women. 3. **De novo Mutation Rates**: In 8,089 sequenced trios from the 100,000 Genomes Project, women with genetic risk of earlier menopause had increased rates of de novo mutations in their offspring, though this association was not replicated in independent samples from the deCODE study. 4. **Replication and Overlap with Common Variants**: The study replicated several associations in independent datasets and found overlap between common and rare variant signals for age at menopause, highlighting the importance of DNA damage response pathways in ovarian ageing. 5. **Biological Mechanisms**: The study revealed novel biological mechanisms, such as the role of *ZNF518A* in regulating genes involved in reproductive longevity and the role of *SAMHD1* in preventing excess deoxynucleotide triphosphates, which is crucial for DNA repair. These findings provide new insights into the genetic architecture of ovarian ageing and its implications for cancer risk and de novo mutation rates.This study investigates the genetic links between ovarian ageing, cancer risk, and de novo mutation rates. By analyzing rare protein-coding variants in 106,973 women from the UK Biobank, the researchers identified genes with effects five times larger than those found for common variants. Key findings include: 1. **Genetic Links to Ovarian Ageing**: Rare variants in genes such as *ZNF518A*, *PNPLAS*, *PALB2*, *SAMHD1*, and *ETA1* were associated with ovarian ageing, with *ZNF518A* showing the strongest effect (5.61 years earlier menopause). These findings reinforce the link between ovarian ageing and cancer susceptibility. 2. **Cancer Risk**: Damaging germline variants in *SAMHD1* were associated with increased all-cause cancer risk in both men and women, particularly for prostate cancer in men and hormone-sensitive cancers in women. 3. **De novo Mutation Rates**: In 8,089 sequenced trios from the 100,000 Genomes Project, women with genetic risk of earlier menopause had increased rates of de novo mutations in their offspring, though this association was not replicated in independent samples from the deCODE study. 4. **Replication and Overlap with Common Variants**: The study replicated several associations in independent datasets and found overlap between common and rare variant signals for age at menopause, highlighting the importance of DNA damage response pathways in ovarian ageing. 5. **Biological Mechanisms**: The study revealed novel biological mechanisms, such as the role of *ZNF518A* in regulating genes involved in reproductive longevity and the role of *SAMHD1* in preventing excess deoxynucleotide triphosphates, which is crucial for DNA repair. These findings provide new insights into the genetic architecture of ovarian ageing and its implications for cancer risk and de novo mutation rates.