In recent years, more than 25 genes have been associated with HBC and new associations are expected to emerge. Most of the identified HBC genes code for proteins involved in genome maintenance pathways, which are connected with BRCA1 and BRCA2. For example, we found genes such as ATM, BARD1, CHEK2, MLH1, PALB2, PTEN, TP53, FANCC and FANCM.

The BRCA1 and BRCA2 genes produce two large proteins which, together with other proteins, such as PALB2, form a molecular complex with DNA repair function. Alteration of the function and structure of BRCA1 and BRCA2 proteins leads to genomic instability and can induce tumor development.

Germline pathogenic variants in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner, i.e. the presence of a single copy of a variant in these genes markedly increases the risk of developing HBC. They are variants that truncate and/or inactivate BRCA1 and BRCA2 proteins and include: nonsense mutations, missense mutations, small insertions or deletions, large rearrangements and splicing alterations.

Breast cancer risk can differ depending on the genes affected, the variants and between families. Due to the number of genes and variants that are being linked to HBC, it is currently not possible to provide an accurate individual risk estimate. However, we can consider that individuals carrying pathogenic variants in the BRCA1 and BRCA2 genes have an increased risk of breast and other cancers.

The risk of both breast and ovarian cancer is estimated to be higher in women carrying pathogenic variants in BRCA1 compared to women carrying variants in BRCA2. Women carrying pathogenic mutations in BRCA1 have a 59% risk of breast cancer and a 34% risk of ovarian cancer at age 70. These risks may vary by population, but are always significantly elevated compared to the risks in the general population. In contrast, men who carry a germline mutation in the BRCA2 gene have an estimated cumulative risk of breast cancer of 7% by the age of 80.

There are several factors that can impact an individual's risk of developing HBC. It is important that your physician or healthcare professional evaluate all of these factors in order to give the most accurate estimate possible of your risk of HBC. Among these factors are:

Age: As we have mentioned, the risk of developing breast cancer depends on age. Generally breast cancers in women with genetic susceptibility appear earlier than in women with sporadic breast cancer.
Family history: the risk of breast cancer increases as the number of first-degree relatives affected by breast, ovarian or other related cancers increases.
Reproductive history: the risk of breast cancer increases when a woman has undergone early menarche and/or late menopause. It is also reduced by the presence of an early full-term pregnancy. Breastfeeding also reduces the risk of breast cancer in BRCA1 mutation carriers.
Oral contraceptives: the use of oral contraceptives reduces the risk of ovarian cancer in the general population and also in carriers of pathogenic variants in the BRCA1 and BRCA2 genes.
Alcohol consumption: alcohol consumption increases the risk of breast cancer.
Other genes: there are other genes that may contribute to the risk of developing breast and ovarian cancer such as TP53, PTEN/MMAC1 and STK11 (for breast and ovarian cancer) and MLH1, MSH2, MSH6 and PMS2 (for ovarian cancer).

In individuals of Ashkenazi Jewish ancestry, the study of three variants BRCA1 c.5266dup (5382insC, rs80357906), BRCA1 c.68_69del (185delAG, rs80357914) and BRCA2 c.5946del (6174delT, rs80359550), which together account for up to 99% of the pathogenic variants identified in this population, is usually recommended. The c.1687C>T (rs80356898) variant in the BRCA1 gene is the most common variant in individuals from Europe. In addition to these three variants, more than 3,000 pathogenic variants in BRCA1 and over 4,000 in BRCA2 have been identified and are listed in the ClinVar and BRCA Exchange databases.

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