Cancer Susceptibility Genes for Gynaecological Cancers

We all have two copies of every gene in our body, inherited from each of our parents. Genes have different functions and instruct our cells to do different things.

High penetrance cancer susceptibility genes are a group of genes that protect the body from developing a cancer, usually through correcting DNA mistakes and repairing DNA copies. If there’s a pathogenic change in one of these genes, it means they won’t be able to function properly. With a gene not working properly some of that protection against cancer is lost. Over time, DNA mistakes can accumulate which puts someone with a change in one of these genes at risk of developing ovarian, endometrial and other related cancers over their lifetime.

Read the genomics toolkit which covers gynaecological cancers.

Below is more information about individual genes and their associated risks if there is a pathogenic change in them.

PALB2 is a gene involved in homologous recombination repair. Heterozygous constitutional (germline) pathogenic variants in PALB2 are associated with increased cancer risks, predominantly breast cancer.

Learn more about PALB2 on GeNotes.

Estimated lifetime cancer risk for carriers of germline pathogenic variants in PALB2

Yang X, Leslie G, Doroszuk A and others. ‘Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families’. J Clin Oncol 2019: volume 38, issue 7, pages 674-685. doi: 10.1200/JCO.19.01907

Nepomuceno, T.C.; De Gregoriis, G.; De Oliveira, F.M.B.; Suarez-Kurtz, G.; Monteiro, A.N.; Carvalho, M.A. The Role of PALB2 in the DNA Damage Response and Cancer Predisposition. Int. J. Mol. Sci. 2017, 18, 1886. https://doi.org/10.3390/ijms18091886

Estimated lifetime cancer risk for carriers of germline pathogenic variants in MSH2

Cancer risk and MSH2 gene mutations (facingyourrisk.org)

Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins (biomedcentral.com)

MSH2: Associated risks

For detail, please see UKCGG: Management Guidelines for MSH2 Mutation Carriers

Dominguez-Valentin M et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med. 2019

Estimated lifetime cancer risk for carriers of germline pathogenic variants in MSH6

MSH6 is a human gene that provides instructions for making the DNA mismatch repair protein MSH6. This protein is involved in the recognition and repair of errors that occur during DNA replication, including mismatches and small insertion-deletion loops. MSH6 forms a complex with another protein, MSH2, to detect and bind to DNA mismatches. This complex then recruits other proteins to repair the mismatch, ultimately preventing mutations that can lead to cancer and other genetic diseases.

Mutations in the MSH6 gene have been linked to Lynch syndrome, a hereditary form of colon cancer, as well as other cancers such as endometrial and ovarian cancers. Individuals with MSH6 mutations may have an increased risk of developing Lynch syndrome-associated cancers at an earlier age compared to individuals with mutations in other DNA mismatch repair genes. In addition, some studies suggest that MSH6 mutations may be associated with an increased risk of other types of cancer, such as pancreatic and prostate cancer.

MSH6: Associated risks

For detail, please see UKCGG: BRCA1 Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals

Learn more about RAD51C on facingourrisk.org

Learn more about RAD51D on facingourrisk.org

Estimated lifetime cancer risk for carriers of germline pathogenic variants in RAD51C & RAD51D

 Both are located on chromosome 17, involved in DNA repair (Homologous Recombination). Increased risk of breast cancer: 20- 40%.

Women with a RAD51C or RAD51D alteration are more likely to develop ‘Triple Negative’ Breast Cancers.