Breast and ovarian cancer, hereditary

Panel testing recommended at Breda Genetics for this condition:

Breast and ovarian cancer (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, PTEN, STK11, TP53)


Breast cancer is a major health priority worldwide. Breast cancer develops when transformed cells in the breast begin to grow out of control. It occurs almost entirely in women, but men can get breast cancer too. Hereditary forms of breast cancer have been deeply investigated for decades and continuous advances in molecular genetics have enabled the discovery of several biochemical and genetic mechanisms underpinning the etiopathology. Hereditary susceptibility to breast cancer also increases the susceptibility to ovarian cancer and sometimes to other forms of cancer, hence it is common to refer to this condition as hereditary breast and ovarian cancer syndrome or hereditary susceptibility to breast and ovarin cancer.

Considering the impact of some profilactic choices in case of the detection of a pathogenic mutation (such as breast and ovary surgical excision), it is of the uttermost importance that genetic testing is performed only on those genes in which mutations have been confirmed to be pathogenic, excluding all genes with unconfirmed association to breast/ovarian cancer (“less is more”). Because of this, Breda Genetics has revised the literature to design a stringent panel and maximize the clinical outcome.

Detailed clinical description

Breast cancer

Breast cancer refers to a malignant tumor that develops from a group of neoplastic cells in the breast which are able to invade surrounding tissues or metastasize to distant areas of the body. Breast cancer may arise from cells of the lobules, which are the milk-producing glands, or from cells of the ducts, the passages that drain milk from the lobules to the nipple (see Image 1). Less commonly, breast cancer can begin in the stromal tissues, which include the fatty and fibrous connective tissues or in other tissues of the breast.

Breast anatomy: lobules and ducts (sagittal section)
Image 1 – Breast anatomy: lobules and ducts, sorrounded by stromal tissues.

To address the histological and anatomopathological heterogeneity of breast cancers, breast cancers have been categorized in two so-called intrinsic subtypes:

  • Luminal subtype: it is characterized by the expression of the estrogen receptor gene and other genes that encode proteins characteristic of the luminal epithelial cells. Up to 60% of breast cancers fall into this category, which is further divided in two subgroups: the luminal A subgroup and the luminal B subgroup, characterized by a differential expression of the estrogen receptor gene, the progesterone receptor gene and proliferation-related genes.
  • Basal-like subtype: it is characterized by the expression of genes encoding for proteins of the basal-myoepithelial cells of the normal breast. It account for 15–20% of breast cancers. Even if a clear immunohistochemical profile of this subtype does not exist, the lack of expression of the oncogene ERBB2 (formerly known also as HER2, human epidermal growth factor receptor 2) is a typical feature. As the basal-like subtype tumours generally lack expression of the estrogen receptor and progesteron receptor genes too, they are also referred to as triple negative breast cancer.
  • HER2-enriched subtype: it is characterized by high expression levels of genes located in the HER2 amplicon at 17q12 (see our BRCA1/BRCA2 deep dive for more details).

In terms of histological types, most BRCA1-associated breast cancers are invasive ductal adenocarcinomas of no special type (NST) and of higher grade than sporadic breast cancers. In terms of the intrinsic subtypes, the majority of the BRCA1 breast cancers can thus be classified as basal-like.

Like BRCA1-associated tumors and sporadic carcinomas, BRCA2-associated breast cancers are mostly invasive ductal adenocarcinomas of NST with a moderate or poor differentiation. However, the overexpression of estrogen receptor, progesteron receptor, CK8, and CK18 assigns BRCA2 tumors to the luminal intrinsic subtype, with the vast majority belonging to the luminal B subtype.

Coming to RAD51C-associated breast cancers, the majority of the patients have intermediate-grade invasive ductal carcinoma. RAD51C-related breast tumors belongs to the intrinsic subtype of luminal A subtype.
CHECK2-associated breast cancers belong to the luminal B subtype.

Controlateral breast cancer can be observed both in hereditary and non-hereditary (sporadic) breast cancer. Studies seem to highlight a tendency in higher rates of controlater breast cancer in women who underwent conservative treatment.  Predictors of controlater breast cancer include age at first breast cancer, family history of early-onset breast cancer, and underlying genetic mutations (the ten-year cumulative contralateral breast cancer risks appears to be around 20% for patients with a BRCA1 mutation and 10% for those with BRCA2 mutation).

Ovarian cancer

Serous adenocarcinomas are a common type of ovarian cancer in women with genetic susceptibility to breast and ovarian cancer. Serous adenocarcinomas are generally of higher grade and exhibit prominent intraepithelial lymphocytes, marked nuclear atypia, and abundant mitoses. It has recently been concluded that most cases of high-grade serous cancers actually arise from the fallopian tubes rather than the ovaries. Conflicting results have been reported from studies on ovarian cancer survival rates in women with and without BRCA1 or BRCA2 mutations, although there appear to be a more favorable survival rate among individuals with a detectable BRCA1 or BRCA2 pathogenic variant compared to individuals without mutations in these genes.

Male breast cancer

The cumulative risk of male breast cancer is higher in males with a BRCA1 or BRCA2 pathogenic mutation than in males without mutations in these genes. Overall, BRCA2 mutations appears to be a greater risk factor (the cumulative risk for men with a BRCA1 mutation at 70 years is 1.2%, whereas the cumulative risk for men with a BRCA2 mutation at 70 years if 6.8%: the cumulative risk for men at 80 years with a mutation in either of the two genes is around 9%).

Other cancers

To a lesser extent, individuals with a genetic mutation in BRCA1 or BRCA2 may develop also other cancers such as prostate cancer, pancreatic cancer, and melanoma. BRCA2 mutations confer a higher risk than BRCA1 mutations for cancers other than breast and ovarian. Other breast and ovarian cancer genes (see below) may confer high risk for additional, specific types of cancer.


Breast cancer is the most common cancer affecting women worldwide. Among women aged under 45 years, breast cancer is the leading cause of cancer-related deaths. 230,815 women and 2,109 men in the USA were diagnosed with breast cancer in 2013, and 40,860 women and 464 men died from it. 358,967 individuals in Europe were diagnosed with breast cancer in 2012, and 90,665 individuals died from it.

Hereditary forms account for approximately 5%–10% of all human breast cancers. The high-susceptibility genes BRCA1 and BRCA2, together with germline mutations in other genes, account for about 45-48% of all hereditary breast and ovarian cancer cases. In about half of the cases of hereditary breast and ovarian cancer, the genetic diagnosis remains elusive, as no mutation can be found in any of the susceptibility genes known thus far.

Molecular genetics


The most frequently mutated genes in hereditary breast and ovarian cancer are BRCA1 and BRCA2. Mutations in these genes account for approximately 25–28% of hereditary breast and ovarian cancers. BRCA1 and BRCA2 related susceptibility to breast and ovarian cancer is inherited in an autosomal dominant manner. Lifetime risks for developing breast cancer in individuals with a pathogenic variant in BRCA1 or BRCA2 are 40%-80% in women and 1%-10% in males. There appears to be no mutational hot spots in the BRCA1 or BRCA2 sequences, although exons 10 to 12 of BRCA1 contain a large proportion of all clinically relevant mutations and are highly important for the tumour suppressor function of BRCA1. This middle part of the BRCA1 sequence is known to interact with several proteins involved in a wide range of cellular pathways such as transcription, DNA repair and cell cycle progression. Rare and recurring mutations have been detected in the BRCA1 and BRCA2 genes, the latter ones mainly deriving from a founder effect, like the BRCA1 mutations c.68_69delAG and c.5266dupC or the BRCA2 mutation c.5946delT in the Ashkenazi Jewish population (see our BRCA1/BRCA2 deep dive for more details).

Women with an abnormal BRCA1 gene have a 50% to 70% risk of developing breast cancer by age 70. Women with an abnormal BRCA2 gene have a 40% to 60% risk of developing breast cancer by age 70.

Other breast and ovarian cancer genes

Germline mutations in other genes with different levels of penetrance account for about 20% of the hereditary breast cancer cases. Most of these genes were initially discovered because breast cancer was a component of a large and specific cancer syndrome. For instance, Li–Fraumeni syndrome (TP53 gene mutations) is an autosomal dominant cancer predisposition syndrome often occuring in childhood or young adulthood which typically lead to soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, leukemias, and pre-menopausal breast cancer.

Image 2 – Proportion of mutations in hereditary breast and ovarian cancer genes.

Taking into account the frequency of mutations (from high to low), immediately after BRCA1 and BRCA2, it comes PALB2 (also causing Fanconi anemia), RAD51D, RAD51C, MMR and BARD1 (see also the “cake” in Image 2). Mutations in the BRIP1 gene, formerly considered to be a (low) risk factor, have been demonstrated to be substantially not associated with increased risk for breast cancer in a large study on more than 48,000 patients drawn from studies participating in the Breast Cancer Association Consortium (BCAC; PMID 26921362).

Regarding the BRCA1 and BRCA2 gene, we invite you to read the BRCA1 and BRCA2 deep dive page here.

PALB2 mutations increases breast cancer risk 5 to 9 times higher than average, almost as high as an abnormal BRCA1 or BRCA2 gene. Women with an abnormal PALB2 gene have a 33% to 58% lifetime risk of developing breast cancer. Notably, women with PALB2 mutations from families with a history of breast cancer seem to have substantially greater breast cancer risk than women with PALB2 mutations but no family history.

RAD51D heterozygous mutations have been identified in families with both breast and ovarian cancer. It has been demonstrated that RAD51 mutations have a higher influence on the risk of ovarian cancer (relative risk: 6.3) than the risk for breast cancer (relative risk: 1.3). Nonsense, frameshift, and missense mutations have been identified.

RAD51C mutations increases the risk for both breast and ovarian cancers. The mean age of onset reports is 53 years (range 33 to 78) for breast cancer and 60 years (range 50 to 81) for ovarian cancer. In the first study on RAD51C, the penetrance of the mutations appeared to be very high (however, caution is warranted as more and more evidence is continously acquired on the effect of pathogenic mutations in the breast and ovarian cancer genes). Invasive and pre-invasive ductal carcinomas are reported, with variable status in regard of estrogen and progesterone receptor status. As for what concerns RAD51C-related ovarian cancers, invasive serous adenocarcinomas and invasive endometrioid adenocarcinoma have been described.

The BARD1 gene has been studies in a group of Finnish families and the mutation c.1670G>C (p.Cys557Ser) was found to be a commonly occurring and mainly breast cancer-predisposing allele. Subsequent functional studies demonstrated the likely damaging effects of the p.Cys557Ser variant and several other putative disease-causing variants in the BARD1 gene. The ClinVar database currently contains more than 40 pathogenic/likely pathogenic variants in the BARD1 gene, including frameshift, missense, nonsense, and splice site mutations. The product of the BARD1 gene is involved in cell growth and division and DNA repair by a mechanism involving a binding to the BRCA1 protein.

We must then keep into account mutations in genes which cause more specific cancer syndromes (usually distincted by additional typical signs and symptoms) or rares tumors. These include:

ATM gene: biallelic mutations in the ATM gene cause ataxia telangiectasia, which is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Healthy carriers of ATM gene mutations (typically the parents of an affected child) have approximately four times the risk of the general population for cancer, primarily because of breast cancer. Cancer risk probably depends on multiple factors including tumor type, age at cancer onset, and whether the individual is heterozygous for a missense or a truncating variant. ATM variants associated with breast cancer tend to be missense changes whereas ATM missense variants in individuals with ataxia telangiectasia only are uncommon (<10%). The risk for breast cancer may be increased by radiation exposure.

CDH1 gene: germline and somatic mutations in the CDH1 gene have been found in lobular breast cancer and hereditary diffuse gastric cancer (HDGC)Hereditary diffuse gastric cancer is an autosomal dominant cancer predisposition syndrome. Heterozygous CDH1 mutation carriers have a 70 to 80% lifetime risk of developing diffuse gastric cancer. In addition to gastric cancer, up to 60% of female mutation carriers develop lobular carcinoma of the breast, and some carriers may develop colorectal cancer. CDH1-related breast cancer may be sporadic, bilateral and arising before 50 years of age. In women from families with history of HDGC and a confirmed CDH1 mutation, the cumulative risk of HDGC and invasive lobular breast cancer by age 80 appears to be 83% and 39%, respectively.

CHEK2 gene: heterozygous mutations in the CHEK2 were originally thought to cause Li-Fraumeni syndrome type 2. Actually, the only gene so far associated to Li-Fraumenti syndrome remains TP53. However, CHEK2 mutations can cause breast cancer in women. In particular, there seems to be some evidence of higher prevalence of the 1100delC mutation among cases with a first-degree relative affected with breast cancer and a trend for higher breast cancer odds ratio at younger ages at diagnosis. CHECK2-associated breast cancers belong to the luminal B subtype.

MRE11A gene: homozygous or compound heterozygous mutation in the MRE11A gene cause  ataxia-telangiectasia-like disorder-1, a rare disease that affects brain development (see also the ataxia-teleangectasia caused by ATM gene mutations). The disease also weakens the immune system and increases cancer risk. Notably, another genetic subtype of this disorder,  ataxia-telangiectasia-like disorder-2, is thought to be caused by mutations in the PCNA gene (although just one such family have been reported to date).

NBN gene: NBN gene mutations causes Nijmegen breakage syndrome, a condition that causes slow growth in infancy and early childhood. Patients with Nijmegen breakage syndrome are shorter than average and have a higher risk of several types of cancer, including breast cancer.

PTEN gene: PTEN gene mutations causes Cowden syndrome, a rare disorder in which patients have a higher risk of both benign and cancerous breast tumors, as well as growths in the digestive tract, thyroid, uterus, and ovaries. The lifetime breast cancer risk for women with a PTEN mutation is up to 85%, with an average age of diagnosis between 38 and 46 years and 50% penetrance by age 50 years.  The earliest documented breast cancer is at age 17 years (which may justify molecular testing in at-risk individuals younger than age 18 years).

STK11 gene: heterozygous mutations in the STK11 gene cause Peutz-Jeghers syndrome, which is an autosomal dominantly inherited condition characterized by melanocytic macules of the lips, buccal mucosa, and digits, multiple gastrointestinal hamartomatous polyps;, and an increased risk of various neoplasms, such as breast, ovarian and lung cancer. Patients may also develop freckling around the eyes, nose, and mouth, as well as inside the mouth.

TP53 gene: Patients with a TP53 mutation are affected by Li-Fraumeni syndrome and are at higher-than-average-risk of breast cancer and several other cancers, including leukemia, brain tumors, and sarcomas (cancer of the bones or connective tissue). The cancer risk in women with a TP53 mutation is up to nearly 100%. In men, it is up to 73%.

RAD50 gene: biallelic mutations in this gene cause Nijmegen breakage syndrome-like disorder. Along with the MRE11A and NBN genes, the RAD50 gene forms the MRN complex, which helps repair DNA damage in cells. An abnormal RAD50 gene has been linked to a higher risk of breast cancer in some families because the abnormal gene stops the cells from repairing damaged DNA.

According to a recent study, MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes, leading to an odd ratio of approximately 3. In these genes, missense substitutions are more frequent than truncating variants (PMID 24894818).

The relationship between breast cancer and Lynch syndrome is unresolved. Lynch syndrome, which is caused by a germline pathogenic variant in one of the so called mismatch repair genes (MMR genes: MLH1, MSH2, MSH6, and PMS2) or in EPCAM, is associated with increased risk for tumors exhibiting microsatellite instability (MSI), such as colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. Controversial results have been so far obtained in association studies about mutations in the Lynch syndrome genes and breast cancer, so there’s no definitive evidence that mutation in the MMR genes may increase the risk for breast cancer. The Lynch syndrome genes might be tested in families where ovarian cancer (together with colon cancer) is manifesting.

Genetic factors in sporadic breast cancer

Rare high/intermediate-penetrance mutations, such as the one found in the above mentioned genes, account for a considerable cases of hereditary breast and ovarian cancer, but they do not shed light on the role of genetics in non-familial (sporadic) breast cancers. Genome-wide association studies (GWAS) have identified over 80 loci  which seem to be significantly associated with sporadic breast cancer. Collectively, however, these variants seem to explain only 16 % of breast cancer susceptibility. For example, significant correlation were found with two polymorphisms of the XRRC3 gene. Other studies suggested a significant correlation in sporadic breast cancer and four intronic polymorphisms in the FGFR2 gene. To date, more than 60 breast cancer GWAS have been performed. However, the risk assessment can be marginally improved by incorporating susceptibility variants from GWAS. Hence, we do not recommend including such genes in multigene panel testing.

Genetic testing strategy

Considering the impact of some profilactic choices in case of the detection of a pathogenic mutation (such as breast and ovary surgical excision), it is of the uttermost importance that genetic testing is performed only on those genes in which mutations have been confirmed to be pathogenic, excluding all genes with unconfirmed association to breast/ovarian cancer (“less is more”). Because of this, Breda Genetics has revised the literature to design a stringent panel and maximize the clinical outcome. If sequencing tests negative, then large delettions/duplications testing must be considered, at least in the BRCA1 and BRCA2 genes. Because there is no clear association between Lynch syndrome and breast cancer, the Lynch syndrome genes have not been included in our panel. Due to the increased risk for ovarian cancer alone, the Lynch syndrome genes may be included when testing families with ovarian cancer only.

Panel testing recommended at Breda Genetics for this condition (EXOME PANEL):

Breast and ovarian cancer (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD51C, RAD51D, PTEN, STK11, TP53)

References:,, PMID 20301488, PMID 20301790PMID 15122511, PMID 20301425, PMID 27716388, PMID 17200668, PMID 25337756, PMID 11729114, PMID 25824734PMID 15342711, PMID 28174632, PMID 20301661PMID 24894818OMIM 602774, OMIM 175200, OMIM 137215, OMIM 610832, OMIM 614291U.S. Cancer Statistics Working Group, European Cancer Observatory.

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