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Family history and genetic factors

A family history of breast cancer means having one or more blood relatives who have, or have had, breast cancer. These relatives could be on either the father’s or mother’s side of the family.

As breast cancer is common, many women will have a family history by chance.  However, some women with a family history may have inherited a faulty gene which increases the risk of cancer. We all inherit a set of genes from each of our parents. Sometimes there is a fault, or mutation, in one copy of a gene which stops that gene working properly and this can lead to an increased risk of breast cancer.

Around 5% of breast cancers can be explained by an inherited gene fault. Genetic changes can also occur during our lifetime. On this page you will find information about family history of breast cancer and other cancers and genetic mutations which are associated with risk of breast cancer.

There are several genes in which mutations may be involved in the development of breast cancer, including rare to very rare high-risk gene mutations such as those in BRCA1 and BRCA2, TP53, PTEN, CDH1 and STK11 and some rare moderate-risk gene mutations such as PALB2, ATM and CHEK2.

If you are concerned about a family history of breast cancer, your general practitioner will be able to help you assess your risk using Cancer Australia’s online familial risk assessment tool.

It may be appropriate for some women who have a strong family history to be referred to a family cancer clinic. Family cancer clinics can provide a more precise risk assessment, advice about genetic testing and an individualised management plan.

Family history of breast cancer

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a family history of breast cancer is associated with an increased risk of breast cancer.

However, most women who develop breast cancer do not have a family history of the disease. Because breast cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Only about 5% of breast cancer can be explained by an inherited gene fault. However, a family history on either the mother’s side or the father’s side increases a woman’s risk of breast cancer.

The significance of a family history of breast cancer increases with the number of family members affected and the younger their ages at diagnosis.

Women with one first-degree relative (parent, sibling or child) who has had breast cancer have about 2 times the risk of breast cancer compared to women with no family history. Women with two first-degree relatives who have had breast cancer have about 3 times the risk. Women with three or more relatives who have had breast cancer have nearly 4 times the risk.

Women with one or more second-degree relative who has had breast cancer have about 1.5 times the risk of breast cancer as women with no family history. A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.

It is important to note that a family history on the father’s side is just as important as on the mother’s side of the family.

The risk is higher if two or more relatives have other characteristics associated with increased risk, such as being diagnosed before age 50 or being of Ashkenazi Jewish descent.

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.Family members have genetic factors in common and this might explain the association between family history of breast cancer and increased breast cancer risk. These genetic factors could include mutations in genes such as BRCA1 or BRCA2.

In addition, family members often have similar environments and lifestyles as each other. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancer.

Evidence classification: Convincing

There is convincing evidence that having a family history of breast cancer is associated with an increased risk of breast cancer.

Women with one first-degree relative (parent, sibling or child) who has had breast cancer are estimated to have 1.80 (95% CI 1.69–1.91) times the risk of breast cancer as women with no family history.1

Women with two first-degree relatives who have had breast cancer are estimated to have 2.93 (95% CI 2.36–3.64) times the risk of breast cancer as women with no family history.1

Women with three or more first-degree relatives who have had breast cancer have about 3.9 (95% CI 2.03–7.49) times the risk of breast cancer as women with no family history.1

Women with one or more second-degree relatives who have had breast cancer are estimated to have 1.5 times (95% CI 1.4–1.6) the risk of breast cancer as women with no family history.2 (A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.)

Mechanisms

Family members share both genetic factors and environmental factors, both of which could contribute to an association between family history of breast cancer and increased risk of breast cancer. Genetic factors could include mutations in genes such as BRCA1 or BRCA2. Environmental factors include exposures, lifestyles and diets.2,3

Evidence 

For women who have one affected first-degree relative (compared with women who have no affected relatives), meta-analyses have estimated a relative risk for breast cancer of 1.80 (95% confidence interval [CI] 1.69–1.91)1 and 2.1 (95% CI 2.0–2.2).2 Two more recent large cohort studies and a case–control study reported a similarly increased risk of breast cancer for women with 1 affected first-degree relative.3-5

For women with two affected first-degree relatives, a relative risk for breast cancer of 2.93 (95% CI 2.36–3.64) has been estimated in a meta-analysis.1 For women with three or more affected first-degree relatives, a relative risk for breast cancer of 3.90 (95% CI 2.03–7.49) has been estimated in the same meta-analysis. Other studies have provided similar estimates of increased risk.2,4,5

For women with one or more affected second-degree relatives, the relative risk of breast cancer (compared with women who have no affected relatives) has been estimated in a meta-analysis as 1.5 (95% CI 1.4–1.6).2

The increased breast cancer risk associated with having a first-degree relative with breast cancer was found to be higher for younger compared with older women in a large meta-analysis1 and in a cohort study.3 One meta-analysis reported inconsistent findings on breast cancer risk according to the age of the person with a family history of breast cancer.2

The increased breast cancer risk associated with having a first-degree relative with breast cancer has also been found to be higher for women whose relative was diagnosed with breast cancer at a younger compared with an older age.1-3,6

Read the full Review of the Evidence

References
  1. Collaborative Group on Hormonal Factors in Breast Cancer (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. Lancet 358(9291):1389–1399.
  2. Pharoah PDP, Day NE, Duffy S, et al. (1997). Family history and the risk of breast cancer: a systematic review and meta-analysis. International Journal of Cancer 71:800–809.
  3. Kharazmi E, Chen T, Narod S, et al. (2014). Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study. Breast Cancer Research and Treatment 144:185–192.
  4. Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
  5. Bevier M, Sundquist K, Hemminki K (2012). Risk of breast cancer in families of multiple affected women and men. Breast Cancer Research and Treatment 132:723–728.
  6. Colditz GA, Kaphingst KA, Hankinson SE et al. (2012). Family history and risk of breast cancer: nurses’ health study. Breast Cancer Research and Treatment 133(3):1097–1104.
Family history of other cancers

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a family history of some cancers other than breast cancer is associated with an increased risk of breast cancer.

The majority of evidence for increased risk of breast cancer for women with a family history of cancers other than breast cancer, exists for family history of ovarian cancer and/or prostate cancer and/or pancreas cancer.

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.

Family members have genetic factors in common and this might explain the association between family history of cancers and increased breast cancer risk. For example, mutations or faults in the BRCA1 and BRCA2 genes increase the risk of ovarian cancer and prostate cancer as well as breast cancer. Faulty BRCA2 genes are also associated with pancreatic cancer. Since relatives share many genes, they also share the risk of cancers associated with the faulty genes.

In addition, family members often have similar environments and lifestyles, such as diet and levels of physical activity. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancers.

Evidence classification: Convincing

There is convincing evidence that a family history of ovarian cancer and prostate cancer and probably some other cancers, including pancreatic cancer, is associated with an increased risk of breast cancer. The more relatives affected, the higher the risk. The risk is also higher if a woman also has a family history of breast cancer.

Mechanisms

Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.

Mutations in genes associated with increased risk of breast cancer are also associated with increased risk of some other cancers. For example, mutations in the BRCA1 and BRCA2 genes also increase the risk of ovarian cancer, and are associated with male breast cancer and prostate cancer. BRCA2 gene mutations are also associated with pancreatic cancer.1

Other gene mutations that increase the risk of both breast cancer and other cancers include PALB2 (pancreatic cancer), TP53 (associated with Li–Fraumeni syndrome and childhood sarcomas), CDH1 (associated with diffuse gastric cancer), PTEN (associated with Cowden syndrome, and thyroid and endometrial cancers) and STK11 (associated with Peutz–Jeghers syndrome, and gastrointestinal, pancreatic and gynaecological cancers). Similar biological mechanisms are likely to increase the risk of breast cancer and these other cancers.

In addition, family members tend to share environments and lifestyles, such as diet and levels of physical activity. Some of these factors are associated with the risk of breast cancer.

Evidence 

Family history of ovarian cancer

The risk of breast cancer in women from families with two or more first‐degree relatives with ovarian cancer has been estimated as 3.74 (95% confidence interval [CI] 2.04–6.28) for women under 50 years of age and 1.79 (95% CI 1.02–2.90) for women 50 years of age and older.2 

From a large, population-based case-control study, the lifetime risks of developing breast cancer for a woman with one or two first-degree relatives with ovarian cancer were estimated to be 14% and 31%, respectively.3

Family history of prostate cancer

A large cohort study and a pooled analysis of case-control studies found that a family history of prostate cancer in a first-degree relative was associated with an increase in breast cancer risk (hazard ratio [HR] 1.14, 95% CI 1.02–1.26 and odds ratio [OR] 1.6, 95% CI 1.1–2.4, respectively).4,5 A family history of both breast and prostate cancer in first-degree relatives was associated with a higher risk of breast cancer (HR 1.78, 95% CI 1.45–2.19).

An increased risk of breast cancer in women with a family history of prostate cancer was also found in a consecutive series study of prostate cancer families.5  Breast cancer risk was higher for women who had more than one relative with prostate cancer, and relatives who were diagnosed with prostate cancer at younger ages.

Family history of pancreatic cancer

About 5% of patients with pancreatic cancer carry germline mutations in BRCA2PALB2 gene mutations are also associated with increased risk of pancreatic cancer.

Family history of colorectal cancer

A large cohort study did not find a significant association between a family history of colorectal cancer and risk of breast cancer after adjustments for a family history of breast and prostate cancer (HR 1.08, 95% CI 0.99–1.19).4 However, a family history of both breast and colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (HR 1.47, 95% CI 1.34–1.61).4

A pooled analysis of case–control studies found that a family history of colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (OR 1.5, 95% CI 1.1–1.9).5 An increased risk of breast cancer has also been found in women with either a first-degree (OR 1.26, 95% CI 1.08–1.45) or a second-degree relative (OR 1.21, 95% CI 1.07–1.36) with colon cancer in a population-based case–control study.7

Family history of other cancers

An association has been found between family history of haemolymphopoietic cancers and increased breast cancer risk in a network of case–control studies from Italy and Switzerland (OR 1.7, 95% CI 1.2–2.4).8

Read the full Review of the Evidence

References
  1. EviQ. 2018 Facts for people and families with a faulty BRCA2 gene https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3427-facts-for-people-and-families-with-a-faulty-b##what-is-the-risk-of-cancer-for-people-with-a-fault
  2. Sutcliffe S, Pharoah PD, Easton DF, et al. (2000) Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. International Journal of Cancer 87(1): 110-117
  3. Claus EB, Risch N, Douglas Thompson W (1993). The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Research and Treatment 28(2):115–120.
  4. Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
  5. Turati F, Edefonti V, Bosetti C, et al. (2013). Family history of cancer and the risk of cancer: a network of case-control studies. Annals of Oncology 24:2651–2656.
  6. Valeri A, Fournier G, Morin V, et al. (2000). Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives. International Journal of Cancer 86:883–887.
  7. Slattery ML, Kerber RA (1993). A comprehensive evaluation of family history and breast cancer risk. JAMA: The Journal of the American Medical Association 270(13):1563–1568.
  8. Turati F, Negri E, La Vecchia C (2014). Family history and the risk of cancer: genetic factors influencing multiple cancer sites. Expert Review of Anticancer Therapy 14(1):1–4.
Single nucleotide polymorphisms

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having certain patterns of single nucleotide polymorphisms (SNPs) or variants in a woman’s DNA may be associated with an increased risk of breast cancer.

Information on a large number of individual SNPs associated with breast cancer risk can be combined into a ‘polygenic risk score’. Women who have the highest ‘score’ using this approach (in a study including 77 SNPs) have about 3 times the risk of breast cancer compared to women who have a score near the middle of the range of scores.

SNPs are normal variations in the genetic material (DNA) in our cells at many single locations (nucleotides) in the DNA. SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in human DNA. Most SNPs have no effect on health. They often act as ‘markers’ of genes that may be associated with a disease, such as breast cancer.

Evidence classification: Convincing

There is convincing evidence that having a high polygenic risk score (PRS), based on certain patterns of a large number of individual single nucleotide polymorphisms (SNPs) or variants across the whole genome, is associated with an increased risk of breast cancer.

Women who have a PRS (based on 77 SNPs) in the highest 1% of the PRS distribution are estimated to have 3.36 times the risk of breast cancer as women in the middle quintile of the distribution (OR 3.36, 95% CI 2.95–3.83).1 Women with a PRS in the lowest 1% of the PRS distribution are estimated to have 0.31 times the risk of breast cancer as women in the middle quintile of the distribution (OR 0.31, 95% CI 0.24–0.39).1

These data may be used in the future to provide more accurate risk prediction than family history alone. They may also be used to influence decisions on cancer risk management for women at high risk of breast cancer.2,3

Mechanisms

SNPs are normal variations in the DNA sequence at many single locations (nucleotides). SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in the human genome. Most SNPs have no effect on health or development. They can act as biological markers of genes that may be associated with a disease such as breast cancer.4

SNPs associated with an increased risk of breast cancer are identified using genome-wide association studies (GWASs), which compare large numbers of SNPs between cases and controls. PRSs for breast cancer risk can then be developed based on combined scores for large numbers of SNPs.1,5

Evidence 

A large GWAS and meta-analysis used an array of more than 500,000 SNPs for genotyping cases and controls.4 It was estimated that 172 common susceptibility variants explain 18% of familial relative risk of breast cancer.4 Another large GWAS estimated that 125 variants explain approximately 14% of the familial risk of oestrogen receptor-negative (ER-) breast cancer.5

A large collaborative case-control study found that the risk of breast cancer was increased for women in the highest 1% of a PRS based on 77 SNPs compared with women in the middle quintile, with an odds ratio (OR) of 3.36 (95% confidence interval [CI] 2.95–3.83).1 Women in the lowest 1% of the PRS distribution had an estimated OR compared with women in the middle quintile of 0.31 (95% CI 0.24–0.39).1 For women in the highest quintile of the PRS, the lifetime risk of breast cancer was 16.6% for women without a family history of breast cancer and 24.4% for women with a first-degree family history.1 For the lowest PRS quintile, women without a family history had a lifetime risk of breast cancer of 5.2%, and women with a family history had a lifetime risk of 8.6%.1

An association between PRS for breast cancer and breast cancer risk has also been found in other studies.2,6,7 For example, a PRS based on 24 SNPs among women from two breast cancer familial cohorts in Australia, Canada, the US and NZ, was associated with increased breast cancer risk, with a hazard ratio [HR] for upper versus lower quintile PRS 3.18 (95% CI 1.84–5.23), and HR for continuous PRS (per standard deviation [SD]) 1.38 (95% CI 1.22–1.56).7

Incorporation of PRSs into models for predicting breast cancer risk has improved the performance of the models.2,7

Read the full Review of the Evidence

References
  1. Mavaddat N, Pharoah PD, Michailidou K, et al. (2015). Prediction of breast cancer risk based on profiling with common genetic variants. Journal of the National Cancer Institute 107(5):1–15.
  2. Li H, Feng B, Miron A, et al. (2016) Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genetics & Medicine 19(1):30–35.
  3. Kuchenbaecker K, McGuffog L, Barrowdale D, et al. (2017) Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. JNCI: Journal of the National Cancer Institute 109(7).
  4. United States National Library of Medicine (2018). Genetics Home Reference: What are genome-wide association studies?, https://ghr.nlm.nih.gov/primer/genomicresearch/gwastudies.
  5. Milne RL, Kuchenbaecker KB, Michailidou K, et al. (2017). Identification of ten variants associated with risk of estrogen receptor-negative breast cancer. Nature Genetics 49(12):1767–1778.
  6. Dite GS, MacInnis RJ, Bickerstaffe A, et al. (2016). Breast cancer risk prediction using clinical models and 77 independent risk-associated SNPs for women aged under 50 years: Australian Breast Cancer Family Registry. Cancer Epidemiology, Biomarkers & Prevention 25(2):359–365.
  7. Shieh Y, Hu D, Ma L, et al. (2016). Breast cancer risk prediction using a clinical risk model and polygenic risk score. Breast Cancer Research and Treatment 159(3):513–525.

 

Rare to very rare, high-risk genes

 

BRCA1 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a mutation or fault in the BRCA1 gene is associated with an increased risk of breast and ovarian cancer.

BRCA1 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 BRCA1 gene has about a 70% chance of developing breast cancer and about a 44% chance of developing ovarian/fallopian tube/primary peritoneal cancer.

Not everyone who has a faulty BRCA1 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 BRCA1 gene fault.

Everyone has two BRCA1 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 BRCA1 gene, or having a BRCA1 mutation. A BRCA1 gene fault can be inherited from either parent.

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

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. EviQ.2018. Facts for people and families with a faulty BRCA1 gene. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3426-facts-for-people-and-families-with-a-faulty-b#what-is-the-risk-of-cancer-for-people-with-a-fault
  3. Hall MJ, Reid JE, Burbidge LA, et al. (2009). BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115(10): 2222–33.
  4. Bahar AY, Taylor PJ, Andrews L, et al. (2001). The frequency of founder mutations in the BRCA1, BRAC2 and APC genes in Australian Ashkenazi Jews: implications for the generality of US population data. Cancer 92(2): 440–445
  5. National Institutes of Health, National Library of Medicine (2018). BRCA1 gene, https://ghr.nlm.nih.gov/gene/BRCA1.
  6. National Cancer Institute (2018). Genetics of breast and gynecologic cancers (PDQ) – health professional version, www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq.
  7. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA: The Journal of the American Medical Association 317(23):2402–2416.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
BRCA2 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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.2,3

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.4 The frequency of BRCA1 and BRCA2 mutations is higher among some ethnic groups, for example Ashkenazi Jewish people.5 These gene mutations occur in 2.5 per cent of Ashkenazi Jews compared to 0.2 per cent of the general population.5

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.6

The BRCA2 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 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.

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. eviQ.2018. Facts for people and families with a faulty BRCA1 gene. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3426-facts-for-people-and-families-with-a-faulty-b#what-is-the-risk-of-cancer-for-people-with-a-fault
  3. eviQ. 2018. Risk management for a female BRCA2 mutation carrier. https://www.eviq.org.au/cancer-genetics/risk-management/162-risk-management-for-a-female-brca2-mutation-ca#evidence-for-risk-management-guidelines
  4. Hall MJ, Reid JE, Burbidge LA, et al. (2009). BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115(10): 2222–33.
  5. Bahar AY, Taylor PJ, Andrews L, et al. (2001) The frequency of founder mutations in the BRCA1, BRAC2 and APC genes in Australian Ashkenazi Jews: implications for the generality of US population data. Cancer 92(2): 440–445
  6. National Institutes of Health, National Library of Medicine (2018). BRCA2 gene, https://ghr.nlm.nih.gov/gene/BRCA2.
  7. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA: The Journal of the American Medical Association 317(23):2402–2416.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
CDH1 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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.2 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).3 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.4 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%).4

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.5,6

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. United States National Library of Medicine (2018). Genetics Home Reference: CDH1 gene, https://ghr.nlm.nih.gov/gene/CDH1.
  3. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  4. Hansford S, Kaurah P, Li-Chang H, et al. (2015). Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncology 1(1):23–32.
  5. Kaurah P, MacMillan A, Boyd N, et al. (2007). Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA: The Journal of the American Medical Association 297(21):2360–2372.
  6. Pharoah PD, Guilford P, Caldas C et al. (2001). Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121:1348–1353.
PTEN Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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.1,2

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.3,4

Pathogenic mutations in PTEN are extremely rare, estimated to occur in approximately one in 200,000 individuals.5

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.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 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).2

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),4 77% (by 70 years of age),7 and 85% (over a lifetime).8

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. United States National Library of Medicine (2018). Genetics Home Reference: PTEN gene, https://ghr.nlm.nih.gov/gene/PTEN.
  4. Nieuwenhuis MH, Kets CM, Murphy-Ryan M, et al. (2014). Cancer risk and genotype–phenotype correlations in PTEN hamartoma tumor syndrome. Familial Cancer 13:57–63.
  5. Ngeow J, Sesock K, Eng C (2017). Breast cancer risk and clinical implications for germline PTEN mutation carriers. Journal of Breast Cancer Research and Treatment 165: 1–8.
  6. eviQ 2018. Risk management for PTEN hamartoma syndrome. https://www.eviq.org.au/cancer-genetics/risk-management/546-risk-management-for-pten-hamartoma-syndrome##lifetime-risk-of-cancer
  7. Bubien V, Bonnet F, Brouste V, et al. (2013). High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. Journal of Medical Genetics 50:255–263.
  8. Tan MH, Mester JL, Ngeow J, et al. (2012). Lifetime cancer risks in individuals with germline PTEN mutations. Clinical Cancer Research 18(2):400–407.
STK11 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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.1-4,5

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.5

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.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 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.6  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.4 

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.2 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).3

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. Giardiello FM, Brensinger JD, Tersmette AC, et al. (2000). Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119:1447–1453.
  3. Resta N, Pierannunzio D, Lenato GM, et al. (2013). Cancer risk associated with STK11/LKB1 germline mutations in Peutz–Jeghers syndrome patients: results of an Italian multicentre study. Digestive and Liver Disease 45:606–611.
  4. Hearle N, Schumacher V, Menko FH, et al. (2006). Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clinical Cancer Research 12(1):3209–3215.
  5. eviQ. 2018. Facts for people and families with Peutz-Jeghers syndrome. https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3431-facts-for-people-and-families-with-peutz-jegh#what-is-the-risk-of-cancer-and-other-features-of-p
  6. United States National Library of Medicine (2018). Genetics Home Reference: STK11 gene, https://ghr.nlm.nih.gov/gene/STK11#.
TP53 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

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.

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.2

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.3,4

The frequency of TP53 gene mutations in the general population is uncertain, with estimates varying from 1 in 20,000 to 1 in 5000.3

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;5 the commonest cancers are soft tissue sarcomas, particularly in children and young adults, and early-onset breast cancer in women.3

Germline TP53 mutations have been found in approximately 4–8% of women with early-onset breast cancer without a family history of LFS.6,7

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.2 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.2

Increased risk of breast cancer has also been found in a pooled analysis8 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.6 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.9

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. Schon K, Tischkowitz M (2017). Clinical implications of germline mutations in breast cancer: TP53. Breast Cancer Research and Treatment 167(2): 417–423.
  4. United States National Library of Medicine (2018). Genetics Home Reference: TP53 gene, https://ghr.nlm.nih.gov/gene/TP53.
  5. eviQ. 2018. Risk management for adults with a TP53 mutation. https://www.eviq.org.au/cancer-genetics/risk-management/749-risk-management-for-adults-with-a-tp53-mutatio##cancer-risk-management-guidelines
  6. Mai PL, Best AF, Peters JA, et al. (2016). Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni Syndrome cohort. Cancer 122(23):3673–3681.
  7. Mouchawar J, Korch C, Byers T, et al. (2010). Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Research 70(12): 4795–4800.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  9. Bougeard G, Renaux-Petel M, Flaman JM, et al. (2015). Revisiting Li–Fraumeni syndrome from TP53 mutation carriers. Journal of Clinical Oncology 33(21):2345–2352.

 

Rare, moderate-risk genes

ATM Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a mutation or fault in the ataxia-telangiectasia mutated (ATM) gene is associated with an increased risk of breast cancer.

ATM is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer. About 1% of men and women carry a fault in ATM*.

Women who have an ATM gene fault have about 1.7 times higher risk of breast cancer compared to women in the general population. There is one specific gene fault associated with a somewhat higher risk of breast cancer. Most women who carry an ATM gene fault will not develop breast cancer.

* If two mutation carriers have a child, there is a 1 in 4 chance that the child will have a very rare, serious condition known as ataxia-telangiectasia (AT). AT is a rare genetic disorder that affects the nervous system and other body systems. It is caused by having two ATM gene faults, one from each parent. Most children with AT are diagnosed between the ages of 1 to 4 years. Carriers of a single mutation in the ATM gene do not get ataxia-telangiectasia.

Evidence classification: Convincing

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

Women who are heterozygous carriers of an ATM mutation are estimated to have 1.74 (95% CI 1.46–2.07) times the risk of breast cancer compared to women without an ATM mutation.1 The risk of breast cancer is higher if a woman carrying the ATM gene mutation has relatives with ataxia-telangiectasia (RR 3.0, 95% CI 2.1–4.5) and the risk is also higher among younger women than older women.2

Mechanisms

The ATM gene codes for a protein that has a key role in DNA repair. Mutations in the gene can allow DNA damage to accumulate, which can lead to formation of cancerous tumours. Approximately 1% of the population are heterozygous carriers of an ATM gene mutation.

Homozygous ATM gene mutations are associated with ataxia-telangiectasia (A-T), a rare autosomal recessive genetic disease occurring in 1 in 40,000 to 1 in 100,000 people, which begins in childhood and affects the nervous system. A-T increases the risk of several cancers, including leukaemia and lymphoma.

Evidence 

Recent studies include a large case-control study using sequencing results of a 25-gene panel from 95,561 women tested clinically for hereditary cancer risk. This study found that heterozygous carriers of an ATM gene mutation had a risk of breast cancer that was 1.74 times (95% confidence interval [CI] 1.46–2.07) higher than in women without the mutation.1 Several other case-control studies and meta-analyses of cohort studies among A-T family members have also found that breast cancer risk is increased in women who are heterozygous carriers of an ATM mutation.

Two meta-analyses of cohort studies2,3 have shown that the increased risk of breast cancer is higher among women with familial A-T who are heterozygous carriers of an ATM mutation (relative risk [RR] 3.0, 95% CI 2.1–4.5 and RR 2.8, 95% CI 2.2–3.7; respectively). The increased breast cancer risk was shown to be substantially higher for heterozygous younger women (aged less than 45–55 years) in A-T families than for women aged older than 55 years in A-T families (RR 7.0, 95% CI 4.1–11.9 versus RR 2.1, 95% CI 1.2–3.6).2

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12
  2. van Os NJ, Roeleveld N, Weemaes CM, et al. (2016). Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline. Clinical Genetics 90:105–117.
  3. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
CHEK2 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.

CHEK2 is considered to be a rare, moderate-risk gene, meaning that a fault in this gene is associated with a moderately increased risk of breast cancer.

Women who have a CHEK2 gene fault have about 2 times the risk of breast cancer compared to women in the general population.

Few women are carriers of a CHEK2 gene fault and most women who carry a CHEK2 gene fault will not develop breast cancer.

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the CHEK2 gene is associated with an increased risk of breast cancer.

Women who are carriers of a CHEK2 mutation are estimated to have 1.99 (95% CI 1.70–2.33) times the risk of breast cancer compared to women without a CHEK2 mutation.1

The estimated risk associated with a CHEK2 gene mutation depends on the specific type of mutation, with the increased risk for the most studied variant, CHEK 1100delC mutation, estimated to be between 2.31 (95% CI 1.88–2.85)2 and 3.10 (95% CI 2.59–3.71)3 times the risk of women without this mutation.

Mechanisms

The CHEK2 gene codes for the checkpoint kinase 2 (CHK2) protein. This protein is a tumour suppressor protein, which prevents cells from growing and dividing too rapidly or in an uncontrolled way.4 Mutations in the CHEK2 gene can allow cells with damaged DNA to continue dividing, leading to the development of cancer.

The CHEK 1100delC mutation, which has been most extensively studied, occurs mainly in individuals of northern and eastern European descent, and has a frequency of approximately 1% in these populations.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 mutations in the CHEK2 gene were associated with increased breast cancer risk.1 The odds ratio (OR) was 1.99 (95% confidence interval [CI] 1.70–2.33), adjusted for family history of breast cancer.

Another large case-control study, using results of germline multigene panel tests found that CHEK2 mutations were associated with an increased risk of breast cancer in women of European ancestry (OR 2.26, 95% CI 1.89–2.72).2

A meta-analysis found an approximately three times increased risk of breast cancer associated with CHEK2 mutations among high-risk women.6 A similarly increased risk associated with CHEK2 mutations was also found in a UK population-based case-control study, with a stronger association found for oestrogen-receptor-positive (ER+) breast cancer than for oestrogen-receptor-negative (ER–) breast cancer.7

Four meta-analyses3,8-10 and a large case-control study2 have indicated that the CHEK 1100delC mutation is associated with increased breast cancer risk, with risk estimates ranging from 2.31 (95% CI 1.88–2.85)2 to 3.10 (95% CI 2.59–3.71)3.

An increased risk of breast cancer has also been found with several other, but not all, specific CHEK2 gene mutations.3,11,12

Read the full Review of the Evidence

References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  3. Zhang B, Beeghly-Fadiel A, Long J, et al. (2011). Genetic variants associated with breast cancer risk: comprehensive field synopsis, meta-analysis, and epidemiologic evidence. Lancet Oncology 21(5):477–488.
  4. United States National Library of Medicine (2018). Genetics Home Reference: CHEK2 gene, https://ghr.nlm.nih.gov/gene/CHEK2.
  5. Meijers-Heijboer, van den Ouweland A, Klijn J, et al. (2002). Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genetics 31(1):55–59.
  6. Aloraifi F, McCartan D, McDevitt T, et al. (2015). Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. Cancer Genetics 208:455–463.
  7. Decker B, Allen J, Luccarini C, et al. (2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of Medical Genetics 54:732–741.
  8. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  9. Yang Y, Zhang F, Wang Y et al. (2012). CHEK2 1100delC variant and breast cancer risk in Caucasians: a meta-analysis based on 25 studies with 29,154 cases and 37,064 controls. Asian Pacific Journal of Cancer Prevention 13:3501–3505.
  10. Weischer M, Bojesen SE, Ellervik C, et al. (2008). CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. Journal of Clinical Oncology 26(4):542–548.
  11. Southey MC, Goldgar DE, Wingvist R, et al. (2016). PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS. Journal of Medical Genetics 53:800–811.
  12. Liu C, Wang Y, Wang QS et al. (2012). The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pacific Journal of Cancer Prevention 13:1355–1360.
PALB2 Gene mutation

Convincing

There is compelling and consistent evidence that the factor increases or decreases the risk of breast cancer.

Having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.

PALB2 is considered to be a rare, moderate-risk gene mutation, meaning that there is a moderately increased risk of breast cancer.

Women who have a PALB2 gene fault have at least 3 times the risk of breast cancer compared to women in the general population. PALB2 gene mutations may also be linked to an increased risk of pancreatic cancer.

Evidence classification: Convincing

There is convincing evidence that having a mutation or fault in the PALB2 gene is associated with an increased risk of breast cancer.

Women who have a PALB2 mutation are estimated to have 3.39 (95% CI 2.79–4.12)1 times the risk of breast cancer compared to women without a PALB2 mutation.1 Higher risks of breast cancer associated with a PALB2 mutation have been estimated in other studies conducted among women with histories suggestive of hereditary breast cancer predisposition.

Mechanisms

The PALB2 gene codes for the ‘Partner and localizer of BRCA2’ (PALB2) protein. The PALB2 protein interacts with the BRCA1 and BRCA2 proteins. This complex plays a key role in DNA repair. Mutations in the PALB2 gene disrupt this repair pathway, and can thereby increase the risk of cancer.2

Approximately 0.2% of the population are estimated to carry a mutation in the PALB2 gene.3

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 PALB2 gene were associated with an increased risk of breast cancer, with an odds ratio [OR] of 3.39 (95% confidence interval [CI] 2.79–4.12), adjusted for family history of cancer.1

A population-based case-control study of 18,575 women in the United Kingdom indicated an odds ratio of 4.69 (95% CI 2.27–9.68) between women with PALB2 mutations and increased breast cancer risk.4

Risk estimates are higher among studies which have included women at higher risk of breast cancer due to a family history of cancer. For example, a large case-control study using results of multigene panel tests among women with clinical histories suggestive of hereditary breast cancer predisposition, found that PALB2 mutations were associated with 6.25 times increased risk of breast cancer (95% CI 4.82–8.14).5

In a meta-analysis6 of three studies, including a study among women with a family history of breast cancer and a germline PALB2 mutation,7 the estimated relative risk of breast cancer associated with PALB2 gene mutations was 5.3 (90% CI 3.0–9.4). A similarly higher estimate of breast cancer risk associated with mutations in the PALB2 gene has also been found in another meta-analysis of case-control studies among high-risk groups of women.8

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References
  1. Kurian AW, Hughes E, Handorf EA, et al. (2017). Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncology 1:1–12.
  2. Cybulski C, Kluźniak W, Huzarshki T, et al. (2015). Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncology 16:638–644.
  3. United States National Library of Medicine (2018). Genetics Home Reference: PALB2 gene, https://ghr.nlm.nih.gov/gene/PALB2.
  4. Decker B, Allen J, Luccarini C, et al. (2017). Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. Journal of Medical Genetics 54:732–741.
  5. Couch FJ, Shimelis H, Hu C, et al. (2017). Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncology 3(9):1190–1196.
  6. Easton DF, Pharoah PDP, Antoniou AC, et al. (2015). Gene-panel sequencing and the prediction of breast-cancer risk. New England Journal of Medicine 372(23):2243–2257.
  7. Antoniou AC, Casadei S, Heikkinen T, et al. (2014). Breast-cancer risk in families with mutations in PALB2. New England Journal of Medicine 371(6):497–506.
  8. Aloraifi F, McCartan D, McDevitt T, et al. (2015). Protein-truncating variants in moderate-risk breast cancer susceptibility genes: a meta-analysis of high-risk case-control screening studies. Cancer Genetics 208(9):455–463.



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