Rare to very rare, high-risk genes

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the BRCA1 (BReast CAncer susceptibility 1) gene is associated with an increased risk of breast cancer.

Women who have a BRCA1 mutation are estimated to have 5.91 (95% CI 5.25–6.67) times the risk of breast cancer compared to women who do not have a BRCA1 mutation.1 The relative risk is estimated to be higher among women with a family history of breast and/or ovarian cancer and among younger women compared with older women.

Women with a BRCA1 mutation have about a 72% chance of developing breast cancer and about a 44% chance of developing ovarian cancer over their lifetime. Men with a BRCA1 mutation have about a 9% chance of developing prostate cancer and about a 1% chance of developing breast cancer over their lifetime.^[2]

Mechanisms

The BRCA1 gene is one of the two most well-known genes associated with risk of breast cancer, the other being BRCA2 (BReast Cancer gene 2). Approximately 1 in 400 to 1 in 800 of the population are estimated to carry a BRCA1 mutation.^[3] The frequency of BRCA1 and BRCA2 mutations is higher among some ethnic groups, for example Ashkenazi Jewish people.^[4] These gene mutations occur in 2.5 per cent of Ashkenazi Jews compared to 0.2 per cent of the general population.^[4]

The increased cancer risk associated with a BRCA1 gene mutation is inherited in an autosomal dominant manner, i.e. the mutation can be inherited from either parent, and both women and men can be carriers.^[5]

The BRCA1 gene codes for a protein that is involved in repairing damaged DNA. Mutations in the gene can allow DNA damage to accumulate.^[6]

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that having a BRCA1 gene mutation was associated with increased odds of breast cancer of 5.91 (95% confidence interval [CI] 5.25–6.67).^[1] The analyses in this study were adjusted for age, ethnicity and family history of cancer.

A study of three prospective cohorts of BRCA1 mutation carriers identified through clinical genetics centresa, and that included Australian families, estimated the lifetime cumulative risk of breast cancer (to age 80 years) among BCRA1-mutation carriers as 72% (95% CI 65%–79%).^[7] Similar cumulative risk estimates have been provided by other studies. The cumulative risk of ovarian cancer (to age 80 years) was 44% (95% CI 36%–53%) for BRCA1 mutation carriers.^[7] 

The incidence of breast cancer for BRCA1 mutation carriers increased rapidly in early adulthood until age 40 years, and then remained at a constant incidence until age 80 years.^[7]

The standardised incidence ratio (SIR) was 16.6 (95% CI 14.7–18.7) for BRCA1 mutation carriers, overall.^[7] (SIR is the ratio of the observed number of cases to the expected number of cases in the population.) SIRs decreased with increasing age. For example, women aged 21–30 years, the SIR was estimated as 73.7 (95% CI 42.9–126.8) and for women aged 71-80 years, the SIR was estimated as 4.8 (95% CI 1.8–12.8).^[7]

The risk of breast cancer in BRCA1 mutation carriers increases with the number of first- and second-degree relatives diagnosed with breast cancer.^[7,8]

1. Mutation carriers identified through clinical genetics centres have a stronger family history of cancer compared with mutation carriers identified through population-based sampling of cases

BRCA2 Gene mutation

Having a mutation or fault in the BRCA2 gene is associated with an increased risk of breast and ovarian cancer.

BRCA2 gene faults are considered to be rare, high-risk gene mutations.

Over the course of her lifetime (up to 80 years of age), a woman who has a faulty BRCA2 gene has about a 69% chance of developing breast cancer and about a 17% chance of developing ovarian/fallopian tube/primary peritoneal cancer.

Not everyone who has a faulty BRCA2 gene will develop cancer. Only 5% of female breast cancers and 15% of invasive epithelial ovarian cancers can be explained by an inherited gene fault.

About 1 in 400 to 1 in 800 people have a BRCA2 gene fault.

Everyone has two BRCA2 genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty BRCA2 gene, or having a BRCA2 mutation. A BRCA2 gene fault can be inherited from either parent.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the BRCA2 (BReast CAncer susceptibility 2) gene is associated with an increased risk of breast cancer.

Women who have a BRCA2 gene mutation are estimated to have 3.31 (95% CI 2.95–3.71) times the risk of breast cancer compared to women who do not have a BRCA2 mutation.^[1] The relative risk is estimated to be higher among women with a family history of breast and/or ovarian cancer and among younger women compared with older women.

Women with a BRCA2 mutation have about a 69% chance of developing breast cancer and about a 17% chance of developing ovarian/ fallopian tube cancer/ primary peritoneal cancer over their lifetime. Men with a BRCA2 mutation have about a 15% chance of developing prostate cancer and about a 7% chance of developing breast cancer over their lifetime. Both men and women with a BRCA2 mutation have a less than 5% chance of developing pancreatic cancer over their lifetime.^[2,9]

Mechanisms

The BRCA2 gene is one of the two most well-known genes associated with risk of breast cancer, the other being BRCA1 (BReast Cancer gene 1). Approximately 1 in 400 to 1 in 800 of the population are estimated to carry a BRCA2 gene fault.^[3] The frequency of BRCA1 and BRCA2 mutations is higher among some ethnic groups, for example Ashkenazi Jewish people.^[4] These gene mutations occur in 2.5 per cent of Ashkenazi Jews compared to 0.2 per cent of the general population.^[4]

The increased cancer risk associated with a BRCA2 gene mutation is inherited in an autosomal dominant manner, i.e. the mutation can be inherited from either parent, and both women and men can be carriers.^[5]

The BRCA2 gene codes for a protein that is involved in repairing damaged DNA. Mutations in the gene can allow DNA damage to accumulate.^[5]

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that having a BRCA2 gene mutation was associated with increased odds of breast cancer of 3.31 (95% confidence interval [CI] 2.95–3.71).^[1] The analyses in this study were adjusted for age, ethnicity and family history of cancer.

A study of three prospective cohorts of BRCA2 mutation carriers identified through clinical genetics centresa, and that included Australian families, estimated the lifetime cumulative risk of breast cancer (to age 80 years) as 69% (95% CI 61–77%) for BRCA2 mutation carriers.^[7] Similar, although generally slightly lower, estimates have been provided by other studies.

The cumulative risk of ovarian cancer (to age 80 years) was 17% (95% CI 11%–25%) for BRCA2 mutation carriers.^[7]

The incidence of breast cancer for BRCA2 mutation carriers increased rapidly in early adulthood until age 50 years, and then remained at a constant incidence until age 80 years.^[7]

The standardised incidence ratio (SIR) was 12.9 (95% CI 11.1–15.1) for BRCA2 mutation carriers, overall.^[7] (SIR is the ratio of the observed number of cases to the expected number of cases in the population.) SIR decreased with increasing age. For example, for women aged 21–30 years, the SIR was estimated as 60.8 (95% CI 25.5–144.9) and for women aged 71–80 years, the SIR was estimated as 6.6 (95% CI 3.1–14.7).^[7]

The risk of breast cancer in BRCA2 mutation carriers increases with the number of first- and second-degree relatives diagnosed with breast cancer.^[7,8]

1. Mutation carriers identified through clinical genetics centres have a stronger family history of cancer compared with mutation carriers identified through population-based sampling of cases.

CDH1 Gene mutation

Having a mutation or fault in the CDH1 gene is associated with an increased risk of invasive lobular breast cancer. This is cancer that develops in the milk-producing glands of the breast.

CDH1 is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer.

Over the course of her lifetime (up to 80 years of age), a woman who has a CDH1 gene fault has about a 42% chance of developing lobular breast cancer. Men and women with a CDH1 gene mutation are also at very high risk of diffuse gastric cancer.

Summary of the evidence

Evidence classification: Convincing (lobular breast cancer)

There is convincing evidence that having a mutation or fault in the CDH1 gene is associated with an increased risk of lobular breast cancer.

Women who have a CDH1 gene mutation are estimated to have 17.7 times (95% CI 7.68–40.1) the risk of lobular breast cancer compared to women who do not have a CDH1 mutation.^[1]

Mechanism

The CDH1 gene codes for the protein epithelial cadherin (E-cadherin), which is found in the membrane that surrounds epithelial cells. E-cadherin is a tumour suppressor protein that prevents cells from growing and dividing too rapidly or in an uncontrolled way.^[10] When the CDH1 gene is faulty, the protein stops working, which can lead to cancer.

Inherited (germline) mutations in the CDH1 gene are also associated with hereditary diffuse gastric cancer (HDGC).

Evidence

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the CDH1 gene were strongly associated with increased risk of lobular breast cancer, with an odds ratio (OR) of 17.7 (95% confidence interval [CI] 7.68–40.10). However, CDH1 mutations were not associated with risk of ductal breast cancer (OR 1.34, 95% CI 0.66–2.68).^[1]

All other studies were not population-based but were based on gene panel tests in, families with hereditary breast cancer disposition, and predominantly among families with known HDGC. 

A case-control study, using results of germline multigene panel tests, found that CDH1 mutations were associated with increased risk of breast cancer (OR 5.34; 95% CI 1.60–20.94).^[11] In a large case series analysis among women with familial CDH1 mutation-positive HDGC, CDH1 germline mutations were associated with increased risk of breast cancer, with relative risks of 7.7 for age 10–49 years and 7.4 for age ≥50 years.^[12] The cumulative risk of breast cancer to age 80 years for women with a CDH1 mutation and familial CDH1 mutation-positive HDGC was 42% (95% CI 23%–68%).^[12]

A similarly increased risk of breast cancer associated with mutations in the CDH1 gene in women with familial HDGC is supported by two smaller studies.^[13,14]

PTEN Gene mutation

Having a mutation or fault in the PTEN gene is associated with an increased risk of breast cancer.

PTEN is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer.

Women who have a PTEN gene fault may have about 6 times the risk of breast cancer compared to women who do not have a PTEN gene fault.

Everyone has two PTEN genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty PTEN gene, or having a PTEN mutation. People with a faulty PTEN gene are known to have Cowden syndrome. Cowden syndrome is part of the PTEN Hamartoma syndrome. PTEN mutations are extremely rare.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the PTEN gene is associated with an increased risk of breast cancer.

Women who have a PTEN gene mutation are estimated to have 5.83 (95% CI 2.43–14.0) times the risk of breast cancer compared to women who do not have a mutation in this gene.1 The large confidence intervals reflect the rarity of PTEN mutations, hence the magnitude of breast cancer risk associated with a PTEN mutation is uncertain.^[1,11]

Lifetime risks have been estimated to be 67% to 60 years of age, 77% to 70 years of age, and 85% over a lifetime.

Mechanism

The PTEN gene codes for a ‘phosphatase and tensin homolog’. This protein acts as a tumour suppressor protein, which helps to prevent cells from growing and dividing too rapidly, or in an uncontrolled way.^[10,15]

Pathogenic mutations in PTEN are extremely rare, estimated to occur in approximately one in 200,000 individuals.^[16]

Cowden syndrome (part of the PTEN hamartoma syndromes) is a rare autosomal dominant condition caused by heritable mutations in the PTEN gene. It is characterised by multiple non-cancerous growths (hamartomas) and an increased risk of developing certain cancers.^[9]

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the PTEN gene were associated with increased odds of breast cancer of 5.83 (95% confidence interval [CI] 2.43–14.0).^[1] The analyses in this study were adjusted for age, ethnicity and family history of cancer.

Another case-control study, using results of germline multigene panel tests of women with histories suggestive of hereditary breast cancer predisposition, also found that PTEN mutations were associated with increased risk of breast cancer (odds ratio [OR] 12.66, 95% 2.01–258.89).^[11]

Several studies have estimated the absolute lifetime risk of breast cancer associated with PTEN gene mutations by comparing breast cancer incidence among women with PTEN Hamartoma Tumour Syndrome (PHTS) and/or an identified PTEN mutation compared to breast cancer incidence in the general population. Risk estimates for absolute lifetime risk of breast cancer were 67% (by 60 years of age),^[15] 77% (by 70 years of age),^[17] and 85% (over a lifetime).^[18]

STK11 Gene mutation

A mutation or fault in the STK11 gene causes a rare genetic disorder known as Peutz–Jeghers Syndrome (PJS). Women with PJS have an increased risk of breast cancer.

STK11 is considered to be a very rare, high-risk gene, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer, including breast cancer.

Women with PJS have about 6 times the risk of breast cancer compared to women in the general population.

Everyone has two STK11 genes (one from their mother, and one from their father). If one of the genes is not working, this is known as having a faulty STK11 gene, or having an STK11 mutation. People with a faulty STK11 gene have Peutz-Jeghers syndrome. PJS is a rare genetic disease that occurs in 1 in 200,000 to 1 in 8300 people.

For women who have a mutation in the STK11 gene in but no clinical signs or symptoms of PJS, the evidence is inconclusive regarding any association with increased risk of breast cancer.

Summary of the evidence

Evidence classifications:

• Convincing (women with Peutz-Jeghers Syndrome)
• Inconclusive (women with STK11 gene mutation but not PJS)

There is convincing evidence that having Peutz–Jeghers Syndrome (PJS) is associated with an increased risk of breast cancer. The majority of women with PJS have a mutation in the STK11 gene.

Women who have PJS are estimated to have about 6 times the risk of breast cancer as the general population.^[1,21,2]

Both men and women with PJS have about a 40% chance of developing bowel cancer and about a 25% chance of developing pancreatic cancer over their lifetime. Women with PJS have about a 45% chance of developing breast cancer and about a 20% chance of developing cervical cancer or ovarian cancer over their lifetime. Not everyone with PJS will develop cancer.^[2]

The evidence for any association between mutations in the STK11 gene in women with no clinical symptoms of 

PJS and risk of breast cancer is inconclusive. Only one large gene panel sequencing study was identified.^[1] No association with breast cancer was found, however only very small numbers of STK11 gene mutations were detected.

Mechanisms

PJS is a rare autosomal dominant genetic disease that occurs in 1 in 200,000 to 1 in 8,300 people. It is associated with noncancerous growths in the gastrointestinal tract and by mucocutaneous pigmentation. It is also associated with increased risk of some types of cancer, especially colorectal cancer. In most people with PJS, the disease is caused by an inherited mutation in the STK11 gene.

The STK11 gene codes for the protein serine threonine kinase 11. This enzyme acts as a tumour suppressor protein – it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the gene can interfere with this function.^[2]

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found no association between mutations in the STK11 gene and invasive breast cancer risk (odds ratio [OR] 4.41, 95% confidence interval [CI] 0.66–29.6).^[1] Only very small numbers of STK11 gene mutations were detected in the panel (5 in all women, and 2 in women with breast cancer).

A systematic review of cancer risk in PJS patients reported increased breast cancer risk (from three studies) associated with PJS.^[22]  The cumulative risk of breast cancer wsa 45% at 70 years of age. One of the included case studies estimated an approximate 6-fold increased risk of breast cancer among 419 women with PJS.^[21] 

Higher risk estimates but with wide confidence intervals have been observed in other studies. A meta-analysis found an increased risk of breast cancer in 104 women with PJS.^[19] The relative risk (RR) of breast cancer in women with PJS was 15.2 (95% CI 7.6–27.0) compared with the general population. A retrospective cohort study also found an increased risk of breast cancer in 119 women with PJS (RR 12.5, 95% CI 5.1–26.0).^[20]

TP53 Gene mutation

Having a mutation or fault in the TP53 gene is associated with an increased risk of breast cancer.

TP53 is considered to be a very rare, high-risk gene mutation, meaning that a fault in this gene is believed to be associated with a significantly increased risk for certain types of cancer, including breast cancer.

Women with a mutation in the TP53 gene have about 5 times the risk of breast cancer as women without the TP53 gene mutation. The increase in risk is higher among women with a mutation in the TP53 gene who are younger than 40 years.

Summary of the evidence

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the TP53 gene is associated with an increased the risk of breast cancer.

Women who have a TP53 mutation are estimated to have 5.37 times the risk of breast cancer compared to women in the general population (OR 5.37, 95% CI 2.78-10.4).^[1] The increased risk of breast cancer associated 

with a TP53 mutation is higher for women at a younger age (≤40 years) than at an older age.^[11]

Mechanisms

TP53 is a tumour suppressor gene that codes for tumour protein p53. The protein has a critical role in the cell in repairing DNA damage and preventing cells from growing in an uncontrolled way.^[23,24]

The frequency of TP53 gene mutations in the general population is uncertain, with estimates varying from 1 in 20,000 to 1 in 5000.^[23]

Inherited mutations in the TP53 gene are associated with Li–Fraumeni syndrome (LFS). LFS is a rare condition inherited in an autosomal dominant pattern. It is characterised by a high lifetime risk of malignancy;^[25] the commonest cancers are soft tissue sarcomas, particularly in children and young adults, and early-onset breast cancer in women.^[23]

Germline TP53 mutations have been found in approximately 4–8% of women with early-onset breast cancer without a family history of LFS.^[26,27]

Evidence 

A large case-control study, using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk, found that mutations in the TP53 gene were associated with an odds ratio (OR) for invasive ductal breast cancer of 5.37 (95% confidence interval [CI] 2.78–10.4).^[1]

Another case-control study, using results of germline multigene panel tests, also found that TP53 mutations were associated with increased risk of breast cancer.^[11] The OR was 2.58 (95% CI 1.39–4.90) overall and 8.25 (95% CI 4.27–15.84) for women aged ≤40 years at diagnosis of breast cancer.^[11]

Increased risk of breast cancer has also been found in a pooled analysis^[8] and a prospective cohort study8 among women with a family history of LFS. The cohort study found a cumulative incidence of breast cancer for women with a TP53 gene mutation of approximately 85% by age 60 years.^[26] In a case series study of French women with a history suggestive of LFS, breast cancer was observed in 79% of women with a TP53 gene mutation, and 31% of these women also developed breast cancer in the other breast.^[28]