Breast 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.

Breast cancer susceptibility genes are a group of genes that protect the body from developing a breast 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 breast and other related cancers over their lifetime.

Read the genomics toolkit which covers breast cancer.

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 by visiting GeNotes: Genomic notes for clinicians.

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

 

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

“On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2% 3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.”

People with an inherited mutation in CHEK2 have increased risk for certain cancers.

Learn more about CHEK2 by visiting the Facing Our Risk website.

Estimated lifetime cancer risk for carriers of germline pathogenic variants in CHEK2:

 

Male CHEK2 pathogenic variant carriers have an increased risk of male breast cancer (approx 1% based on limited data), and could be linked to an increased risk of other cancers.

CHEK2 stands for Checkpoint Kinase 2. The gene is located on chromosome 22. CHEK2 helps control how cells divide. Increased risk of breast cancer: 20-40%.

CHEK2 Gene - GeneCards | CHK2 Protein | CHK2 Antibody

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.

RAD51C and RAD51D

Surveillance:

• Breast: Should be based on individualised risk assessment using tools such as CanRisk *, and in accordance with NICE guidelines on familial breast cancer (CG164).
  • Moderate risk surveillance (lifetime risk of 17-29%): annual mammograms 40 49 years then NHSBSP
  • High risk surveillance (lifetime risk of ≥30% but <40%): annual mammograms 40-59 years then NHSBSP
  • Very high risk surveillance (lifetime risk of ≥40% and 10 year risk of 8% 25 29 yrs , 30 39 years or 12% 40 49 years ): refer to VHR breast screening programme
• Tubo-Ovarian: Not currently recommended. No evidence based screening programme. Should be offered only as part of an ethically approved research study

Risk reducing surgery:

• Tubo-Ovarian: For RAD51C and RAD51D carriers with ≥5% lifetime risk, RRSO should be considered from 50 years. It can be considered in carriers younger than 50 years following individualised risk assessment*, including assessment of menopausal symptoms and shared decision making.
• Risk reducing early salpingectomy with delayed oophorectomy should currently only be offered in the context of a research study
• Breast: Consider discussion of risk reducing mastectomy if lifetime risk ≥30%, in conjunction with an individualised risk assessment* and appropriate counselling.

*Individualised breast, contralateral breast and ovarian cancer risk estimates which incorporate germline PV carrier status, personal risk factors and where relevant breast cancer receptor status, polygenic risk score and breast density, are available at https://canrisk.org/ (Lee et al., 2021) SOURCE: www.ukcgg.org

For more detail, view the UKCGG leaflets and guidelines.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2

Breast: Should be based on individualised risk assessment using tools such as CanRisk*, and in accordance with NICE guidelines on familial breast cancer (CG164).

• Moderate risk surveillance (lifetime risk of 17-29%): annual mammograms 40-49 years then NHSBSP
• High risk surveillance (lifetime risk of ≥30% but <40%): annual mammograms 40-59 years then NHSBSP
• Very high risk surveillance (lifetime risk of ≥40% and 10 year risk of 8% 25-29 yrs , 30-39 years or 12% 40-49 years ): refer to VHR breast screening programme

Hanson, H., Kulkarni, A., Loong, L., Kavanaugh, G. et al. “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. 2022; 0: 1 13. doi : 10.1136/jmg 2022 108898