Cancer Susceptibility Genes for Gynaecological Cancers
What are cancer susceptibility genes?
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.
Below is more information about individual genes and their associated risks if there is a pathogenic change in them.
BRCA1 and BRCA2
BRCA1 and BRCA2 are genes involved in DNA repair. Constitutional (germline) pathogenic variants in these genes are associated with hereditary breast and ovarian cancer, as well as other cancers.
Learn more about BRCA1 and BRCA2 on GeNotes.
BRCA1
Estimated lifetime cancer risk for carriers of germline pathogenic variants in BRCA1 and BRCA 2
Kuchenbaecker KB, Hopper JL, Barnes DR and others. 'Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers'. JAMA 2017: volume 317, issue 23, pages 2402·2416. doi: 10.1001/jama.2017.7112
Cumulative cancer risk per age bracket for a female carrying a BRCA1 germline pathogenic variant (UKCGG)
| Age (years) | Breast Cancer | Ovarian Cancer |
|---|---|---|
| 21 - 30 | 4% | - |
| 31 - 40 | 24% | 2% |
| 41 - 50 | 43% | 8% |
| 51 - 60 | 56% | 20% |
| 61 - 70 | 66% | 41% |
| 71 - 80 | 72% | 44% |
Population lifetime risk of ovarian cancer: 2%
Population lifetime risk of endometrial cancer: ~3%
Other Cancers: Risk for those with PV in BRCA1
| Cancer Type | BRCA1 | Population |
|---|---|---|
| Male Breast | 0.4% | Rare |
| Prostate | 17% | 12% |
| Pancreatic | 3% | 2% |
For more detail, please see UKCGG: BRCA1 Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals.
BRCA 2
Cumulative cancer risk per age bracket for a female carrying a BRCA2 germline pathogenic variant (UKCGG)
| Age (years) | Breast Cancer | Ovarian Cancer |
|---|---|---|
| 21 - 30 | 4% | - |
| 31 - 40 | 13% | <0.5% |
| 41 - 50 | 35% | 1-2% |
| 51 - 60 | 53% | 7% |
| 61 - 70 | 61% | 15% |
| 71 - 80 | 69% | 17% |
Population lifetime risk of ovarian cancer: 2%
Population lifetime risk of endometrial cancer: ~3%
Other Cancers: Risk for those with PV in BRCA2
| Cancer Type | BRCA2 | Population |
|---|---|---|
| Male Breast | 4% | Rare |
| Prostate | 41% | 18% |
| Pancreatic male | 4-5% | 2% |
| Pancreatic female | 2% | 2% |
For more detail, please see UKCGG: BRCA2 Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals.
PALB2
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
MLH1
Estimated lifetime cancer risk for carriers of germline pathogenic variants in MLH1
Cancer risks for MLH1 and MSH2 mutation carriers - PMC (nih.gov)
Cancer Risk Associated with Inherited MLH1 Mutations (facingyourrisk.org)
Structural destabilization and chaperone-assisted proteasomal degradation of MLH1 as a mechanism for Lynch syndrome
MLH1: Associated risks
For detail, please see UKCGG: Management Guidelines for MLH1 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
MSH2
Estimated lifetime cancer risk for carriers of germline pathogenic variants in MSH2
Cancer risk and MSH2 gene mutations (facingyourrisk.org)
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
BRIP1
Estimated lifetime cancer risk for carriers of germline pathogenic variants in BRIP1
The name BRIP1 stands for "BRCA1 Interacting Protein 1." This gene is located on chromosome 17. BRIP1 works with BRCA1 to repair DNA damage. Although the two genes work together, the effects of a mutation are different; people with a BRIP1 mutation do not have the same cancer risk as people with a BRCA1 mutation.
Inheriting a variant on both copies of the BRIP1 gene (one from each parent) can lead to a very rare condition called ‘Fanconi Anemia (FA)’ , which is characterized by bone marrow failure, developmental abnormalities, and an increased risk of cancer.
MSH6
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
PMS2
Estimated lifetime cancer risk for carriers of germline pathogenic variants in PMS2
The PMS2 (PMS1 homolog 2, mismatch repair system component) gene is located on chromosome 7. The PMS2 gene protein plays an important role in repairing DNA damage. Inherited alterations in PMS2 are associated with Lynch Syndrome. Therefore people with an inherited PV in PMS2 are potentially at risk of many cancers, but particularly, colorectal and endometrial cancers.
PMS2: Associated risks
For detail, please see UKCGG: Management Guidelines for PMS2 Mutation Carriers
RAD51C and RAD51D
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.
Management recommendations
BRCA1
For detail, please see UKCGG: BRCA1Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals.
BRCA2
For detail, please see UKCGG: BRCA2Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals.
MLH1
For detail, please see UKCGG: Management Guidelines for MLH1 Mutation Carriers
MSH2
For detail, please see UKCGG: Management Guidelines for MSH2 Mutation Carriers
MSH6
For detail, please see UKCGG: BRCA1 Germline Pathogenic Variant Carriers Management Guidelines for Healthcare Professionals
PMS2
For detail, please see UKCGG: Management Guidelines for PMS2 Mutation Carriers
RAD51C
For detail, please see UKCGG: Management Guidelines for RAD51C Mutation Carriers
RAD51D
For detail, please see UKCGG: Management Guidelines for RAD51D Mutation Carriers
Resources and reading list
Miscellaneous
- Hereditary Hub | Ovarian Cancer Action
- Hereditary Cancer Risk Tool: Explore Your Risk with the Hereditary Cancer Risk Tool | Ovarian Cancer Action
Podcasts
- The G Word, Genomics England
- Genetics Unzipped, The Genetics Society
- The Eve Appeal Podcast: #WombWednesday
- RCGP CIRC Podcast: An Intro to Basic Genomics Terminology
Webinars and lectures
- Preventing Cancer in Jewish Communities | Ovarian Cancer Action
- Genetics and targeted therapies in ovarian cancer | Target Ovarian Cancer (register for free with the ‘Nurses Network’ to access)
- Harnessing the Power of Clinical Nurse Specialists in the Roll Out of Genomics | East Genomics
- DNA Graffiti: The Francis Crick Lecture 2022, Professor Serena Nik-Zainal | The Royal Society
- Advances in Clinical Genomics (3 webinars) | Front Line Genomics
- Royal Society of Medicine Live with Professor Dame Lesley Fallowfield | RSM
- What Are BRCA Gene Mutations? | Ovarian Cancer Action
- From Niche to Necessity, Mainstreaming BRCA+ Testing | Macmillan Cancer Support
Videos
- Why is your BRCA alteration status important to know if you have ovarian cancer? - Youtube | Eve Appeal
Posters
Further resources
- Mismatch repair deficiency and microsatellite instability — Knowledge Hub | GeNotes
- Lynch syndrome — Knowledge Hub | GeNotes
- Lynch Syndrome online training for primary care clinicians | RM Partners
- Lynch Syndrome | The Eve Appeal
- Testing strategies for Lynch syndrome in people with endometrial cancer | NICE
- UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2 [PDF]
- The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome | PMC (nih.gov)
Reading list
- Calzone, K. A., Kirk, M., Tonkin, E., Badzek , L., Benjamin, C., & Middleton, A. (2018). The global landscape of nursing and genomics. Journal of Nursing Scholarship, 3), 249 256 https://doi.org/10.1111/jnu.12380
- Coulson J. (2022). ‘Understanding the role of genomics in nursing practice.’ Nursing standard (Royal College of Nursing (Great Britain) Britain), 10.7748/ns.2022.e12053. Advance online publication. https://doi.org/10.7748/ns.2022.e12053
- Cuthill, V. (2023), ‘Demystifying Genomics in Cancer Care’, Macmillan Cancer Support. Available at: Demystifying genomics in cancer care | Macmillan Cancer Support
- Georgiou, D., Monje Garcia, L., Miles, T., Monahan, K., Ryan, N. (2023) ‘A Focused Clinical Review of Lynch Syndrome’, Cancer Management and Research , 15 (67 85), doi:10.2147/CMAR.S283668
- Hanson, H., Kulkarni, A., Loong, L., Kavanaugh, G. et al. (2022) ‘UK consensus recommendations of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2 .’ Journal of Medical Genetics, BMJ . 0: 1 13. doi : https://doi.org/10.1136/jmg 2022 108898
- Launer , J. (2021)’Effective Clinical Conversations: The Art of Curiosity’ Postgrad Med J , 97, pp 339 340. DOI: Effective clinical conversations: the art of curiosity (bmj.com)
- NHS England, (2022) ‘Accelerating genomic medicine in the NHS’, NHS England. Available at: NHS England » Accelerating genomic medicine in the NHS
- Patch, C. & Middleton, A. (2018) ‘Genetic counselling in the era of genomic medicine’, British Medical Bulletin , 126(1), 27 36. DOI: https://doi.org/10.1093/bmb/ldy008
- Pichini, A & Bishop, M. (2022) ‘A nationally agreed cross professional competency framework to facilitate genomic testing’ Genetics in Medicine. 24(8), 1743 1752. DOI: https://doi.org/10.1016/j.gim.2022.04.023
- Ryan, NAJ., et al (2019) ‘The proportion of endometrial cancers associated with Lynch Syndrome: a systematic review of the literature and meta analysis.’ Genetics in Medicine. 21 (10), 2167 2180. DOI: https://doi.org/10.1038/s41436 019 0536 8
- Sobocan, M., Chandrasekaran, D., Sideris, M. et al. (2023) “Patient decision aids in mainstreaming genetic testing for women with ovarian cancer: A prospective cohort study” British Journal of Obstetrics and Gynaecology , 00:1 10. Accessible at: DOI: 10.1111/1471 0528.17675
- Yang, Xin et al. “Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 38,7 (2020): 674 685. doi:10.1200/JCO.19.01907