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BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Synonym: BRCA1- and BRCA2-Associated HBOC

, MS, , MD, PhD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Revision: September 21, 2023.

Estimated reading time: 57 minutes

Summary

Clinical characteristics.

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The risk of developing an associated cancer varies depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.

Diagnosis/testing.

The diagnosis of BRCA1- and BRCA2-associated HBOC is established in a proband by identification of a heterozygous germline pathogenic variant in BRCA1 or BRCA2 on molecular genetic testing.

Management.

Treatment of manifestations: Treatment of breast cancer per oncologist with consideration of bilateral mastectomy as a primary surgical treatment of breast cancer because of elevated rate of ipsilateral and contralateral breast cancer; PARP inhibitors may be considered in BRCA1- and BRCA2-related tumors. Melanoma treatment per dermatologist and oncologist.

Prevention of primary manifestations: Prophylactic bilateral mastectomy, prophylactic oophorectomy, and chemoprevention (e.g., tamoxifen) have been used for breast cancer prevention, but have not been assessed by randomized trials in high-risk women. Prophylactic salpingectomy followed by delayed oophorectomy or salpingo-oophorectomy for ovarian cancer prevention.

Surveillance: Breast cancer screening in women relies on a combination of monthly breast self-examination, annual or semiannual clinical breast examination, annual mammography, and breast MRI. Annual transvaginal ultrasound and serum CA-125 concentration beginning at age 35 years may be considered for ovarian cancer screening. However, this screening has not been effective in detecting early-stage ovarian cancer, either in high-risk or average-risk women. For men, breast cancer screening includes breast self-examination education and training and annual clinical breast examination beginning at age 35. Annual serum prostate-specific antigen and digital rectal exam screening should begin at age 45. Screening for melanoma should be individualized based on the family history. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended.

Evaluation of relatives at risk: Once a cancer-predisposing BRCA1 or BRCA2 germline pathogenic variant has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial pathogenic variant and thus need increased surveillance and specific treatments when a cancer is identified.

Genetic counseling.

BRCA1- and BRCA2-associated HBOC is inherited in an autosomal dominant manner. The vast majority of individuals with a BRCA1 or BRCA2 pathogenic variant inherited it from a parent. However, because the penetrance of breast, ovarian, and other cancers associated with pathogenic variants in BRCA1 and BRCA2 is less than 100%, not all individuals with a BRCA1 or BRCA2 pathogenic variant have a parent affected with cancer. The offspring of an individual with a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the pathogenic variant. Once a cancer-predisposing BRCA1 or BRCA2 germline variant has been identified in a family, prenatal and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) should be suspected in individuals with a personal or family history (first-, second-, or third-degree relative in either lineage) of any of the following:

  • Breast cancer diagnosed at or before age 50 years
  • Ovarian cancer
  • Multiple (i.e., >1) primary breast cancers in either one or both breasts
  • Male breast cancer
  • Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer
  • The combination of pancreatic cancer and/or prostate cancer (metastatic or Gleason score ≥7) with breast cancer and/or ovarian cancer
  • Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
  • Two or more relatives with breast cancer, one diagnosed at or before age 50 years
  • Three or more relatives with breast cancer at any age
  • A family member with a known BRCA1 or BRCA2 pathogenic variant

Note: (1) "Breast cancer" includes both invasive cancer and ductal carcinoma in situ. (2) "Ovarian cancer" includes epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

Probability Models for BRCA1 and BRCA2 Pathogenic Variants

Several models have been developed to estimate the likelihood that an individual or family has a germline pathogenic variant in BRCA1 or BRCA2 [Parmigiani et al 1998, Frank et al 2002, Antoniou et al 2004, Evans et al 2004, Tyrer et al 2004]. Even among experienced providers, the use of probability models has been shown to increase the ability to identify which individuals are more likely to have a BRCA1 or BRCA2 pathogenic variant [Euhus et al 2002, de la Hoya et al 2003]. For more information about probability models for BRCA1 and BRCA2 pathogenic variants, click here.

Establishing the Diagnosis

The diagnosis of BRCA1- and BRCA2-associated HBOC is established in a proband by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in BRCA1 or BRCA2 on molecular genetic testing (see Table 1).

Note: (1) Molecular testing is most likely to be informative in an individual with a BRCA1- or BRCA2-associated cancer (e.g., breast cancer at age <50 years, ovarian cancer; this individual is often referred to as the "best test candidate." Thus, molecular genetic testing ideally should be performed initially on the "best test candidate" as opposed to a family member who may have an unrelated cancer or who may not have a personal history of cancer. (2) If the best test candidate is not available, molecular testing may be performed on another individual, without a cancer history, with the understanding that failure to detect a pathogenic variant does not eliminate the possibility of a BRCA1 or BRCA2 pathogenic variant being present in the family. (3) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (4) Identification of a heterozygous BRCA1 or BRCA2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include a BRCA1 and BRCA2 gene panel and use of a multigene panel:

  • BRCA1 and BRCA2 gene panel. Sequence analysis of BRCA1 and BRCA2 is performed concurrently with deletion/duplication analysis.
    Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three BRCA1 and BRCA2 pathogenic founder variants: BRCA1 c.68_69delAG (BIC: 185delAG) BRCA1 c.5266dupC (BIC: 5382insC), and BRCA2 c.5946delT (BIC: 6174delT), which together account for up to 99% of pathogenic variants identified in individuals of Ashkenazi Jewish ancestry. If no pathogenic variant is identified by targeted analysis, it may be appropriate to proceed with sequence analysis and deletion/duplication analysis of BRCA1 and BRCA2 or a multigene panel.
    Note: In a family known to have a BRCA1 or BRCA2 germline pathogenic variant, relatives at risk may only need testing for the family-specific germline pathogenic variant, except in the following situations:
    • Individuals of Ashkenazi Jewish descent should consider testing for all three founder pathogenic variants because of the high population frequency of these variants as well as reports of the coexistence of more than one founder variant in some families. They may also consider multigene panel testing, depending on their personal and family history.
    • Individuals with a familial BRCA1 or BRACA2 pathogenic variant on one side of the family and characteristics of HBOC or another inherited cancer syndrome on either the same side or the other side of the family may consider sequence analysis and deletion/duplication analysis of BRCA1 and BRCA2 or a multigene panel, which would detect the familial germline pathogenic variant (if present) and also address whether another germline pathogenic variant may be present.
  • A multigene panel that includes BRCA1, BRCA2, and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Gene 1Proportion of BRCA1- & BRCA2-Associated HBOC Attributed to Pathogenic Variants in GeneProportion of Pathogenic Variants 2 Detected by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
BRCA1 66%87%-89% 511%-13% 5
BRCA2 34%97%-98% 52%-3% 5

HBOC = hereditary breast and ovarian cancer

1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

Clinical Characteristics

Clinical Description

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is characterized by an increased risk for male and female breast cancer, ovarian cancer (including fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate, pancreatic, and melanoma, primarily in individuals with a BRCA2 pathogenic variant. Estimates of malignancy risk vary considerably depending on the context in which they were derived. Table 2 is a summary of the risk for malignancy in an individual with a germline BRCA1 or BRCA2 pathogenic variant.

Table 2.

Risk of Malignancy in Individuals with a Germline BRCA1 or BRCA2 Pathogenic Variant

Cancer TypeGeneral Population RiskRisk for Malignancy 1
BRCA1 BRCA2
Breast 12%55%-72% by age 7045%-69%
Contralateral breast cancer 2% w/in 5 yrs20%-30% w/in 10 yrs; 40%-50% w/in 20 yrs
Ovarian 1%-2%39%-44%11%-17%
Male breast 0.1%1%-2%6%-8%
Prostate 6% by age 69 yrs21% by age 75 yrs;
29% by age 85 yrs
27% by age 75 yrs;
60% by age 85 yrs
Pancreatic 0.5%1%-3%3%-5% by age 70 yrs
Melanoma (cutaneous & ocular) 1.6%Elevated risk

Breast cancer. Compared to sporadic tumors, BRCA1-related tumors show an excess of medullary histopathology, are of higher histologic grade, are more likely to be estrogen receptor negative and progesterone receptor negative, and are less likely to demonstrate human epidermal growth factor receptor 2 overexpression; thus, BRCA1-related tumors fall within the category of "triple-negative" breast cancer [Rakha et al 2008, Lee et al 2011, Mavaddat et al 2012] and overlap with basal-like breast cancers.

The histologic characteristics of BRCA2-related tumors have been inconsistent but appear to be more heterogeneous and are less well characterized than BRCA1-related tumors. They are generally estrogen and progesterone receptor positive; however, a large international series of 2,392 individuals with BRCA2 germline pathogenic variants found that 16% had triple-negative tumors [Mavaddat et al 2012].

The evidence that a germline BRCA1 or BRCA2 pathogenic variant is associated with poor survival in individuals with breast cancer has been inconsistent [Verhoog et al 2000, Bordeleau et al 2010, van den Broek et al 2015, Zhong et al 2015].

Contralateral breast cancer (CBC). Several studies have reported higher rates of CBC [Metcalfe et al 2011a, Vichapat et al 2012, van den Broek et al 2015] in women treated conservatively. Predictors of CBC include age at first breast cancer, family history of early-onset breast cancer, and the affected BRCA gene [Graeser et al 2009, Malone et al 2010, Metcalfe et al 2011a, van den Broek et al 2015]. The risk of CBC is greatest among women whose initial breast cancer occurs at a young age. Most studies show an excess of CBC among individuals with a BRCA1 pathogenic variant when compared to individuals with a BRCA2 pathogenic variant. The risk for CBC was decreased among women who had undergone prophylactic oophorectomy [Metcalfe et al 2011a]; there was no clear association between the use of radiation therapy and an increased risk of CBC in individuals with a BRCA1 or BRCA2 pathogenic variant.

Ipsilateral breast cancer. Two case-control studies reported significantly higher rates of ipsilateral breast cancer in individuals with a germline BRCA1 or BRCA2 pathogenic variant compared with sporadic controls [Haffty et al 2002, Seynaeve et al 2004], however, other studies have not found an increased risk for ipsilateral breast cancer in those with a germline BRCA1 or BRCA2 pathogenic variant when compared with women who had sporadic breast cancer [Robson et al 2004, Graeser et al 2009] and also demonstrated a significant ipsilateral breast cancer risk reduction in individuals receiving radiation therapy compared with those who did not receive radiation therapy [Metcalfe et al 2011b].

Ovarian cancer (including fallopian tube and primary peritoneal cancers). An excess of serous adenocarcinomas as opposed to mucinous or borderline tumors have been observed in women with germline BRCA1 or BRCA2 pathogenic variants [Liu et al 2012, McLaughlin et al 2013]. Serous adenocarcinomas are generally of higher grade and exhibit prominent intraepithelial lymphocytes, marked nuclear atypia, and abundant mitoses [Fujiwara et al 2012]. Most high-grade serous cancers arise from the fallopian tubes rather than the ovaries [Daly et al 2015].

Studies on ovarian cancer survival in women with a germline BRCA1 or BRCA2 pathogenic variant have yielded conflicting results. A pooled analysis of 26 observational studies found a more favorable survival rate among individuals with a BRCA1 or BRCA2 pathogenic variant compared to individuals without a BRCA1 or BRCA2 pathogenic variant. These results persisted when controlling for stage, grade, histology, and age at diagnosis [Bolton et al 2012]. A large population-based case-control study found a higher response to platinum-based therapy, longer progression-free survival, and improved overall survival among individuals with a germline BRCA1 or BRCA2 pathogenic variant [Alsop et al 2012]. Similarly, individuals with platinum-sensitive epithelial ovarian tumors were more likely to have a germline BRCA1 or BRCA2 pathogenic variant than individuals with platinum-resistant tumors [Dann et al 2012]. In a large series of unselected individuals with ovarian cancer, the short-term survival of individuals with ovarian cancer with a germline BRCA1 or BRCA2 pathogenic variant was better than that of individuals without an identified BRCA1 or BRCA2 pathogenic variant; however, the survival advantage was short lived and did not lead to a long-term survival benefit [McLaughlin et al 2013].

Male breast cancer. The majority of BRCA1- and BRCA2-associated male breast cancers, particularly those associated with BRCA2 pathogenic variants, are high grade, hormone receptor positive, and associated with lymph node metastases. Despite having high-grade histology, males with BRCA1- or BRCA2-associated breast cancer have demonstrated a favorable five-year survival [Ibrahim et al 2018].

Prostate cancer. BRCA2-related prostate cancer is more likely to be associated with features of aggressive disease, including a higher tumor stage and/or higher grade at diagnosis, higher Gleason scores [Gallagher et al 2010], and a higher prostate-specific antigen level at diagnosis [Ibrahim et al 2018].

Pancreatic cancer. BRCA1 and BRCA2 are among the most common of the known genetic causes of hereditary pancreatic ductal adenocarcinoma (PDAC) with a mean age at diagnosis of approximately 60.3 years (range 33-83 years) [Golan et al 2014]. There is accumulating evidence of increased sensitivity to platinum-based therapy and poly ADP ribose polymerase (PARP) inhibitors in BRCA1- and BRCA2-associated PDAC [Kowalewski et al 2018].

Melanoma. The risk for melanomas of both the skin and eyes is elevated in individuals with a BRCA2 pathogenic variant [Breast Cancer Linkage Consortium 1999, Hearle et al 2003, van Asperen et al 2005, Gumaste et al 2015]. An analysis of 490 families with BRCA1 or BRCA2 pathogenic variants showed an increased risk for uveal melanoma in individuals with germline BRCA2 pathogenic variants [Moran et al 2012].

Other cancers. Individuals with BRCA1 and BRCA2 pathogenic variants may be at a higher risk for additional malignancies. Furthermore, women with a BRCA1 pathogenic variant may have an elevated risk for serous uterine cancer, but the data are not conclusive [de Jonge et al 2017].

No associated benign tumors or physical abnormalities are presently known to be associated with pathogenic variants in BRCA1 or BRCA2.

Phenotype Correlations by Gene

Ovarian cancer and primary papillary serous carcinoma of the peritoneum are considerably more common and tend to develop at an earlier age in women with a germline BRCA1 pathogenic variant as compared to women with a germline BRCA2 pathogenic variant [Casey et al 2005, Yates et al 2011]. Those with BRCA2 pathogenic variants tend to be at greater risk for male breast cancer [Evans et al 2010], prostate cancer [Mersch et al 2015], pancreatic cancer [Dagan 2008], and melanoma.

Genotype-Phenotype Correlations

BRCA1 and BRCA2 genotype-phenotype correlations have been identified. Such correlations are not currently used in individual risk assessment and management but may be in the future with appropriate validation.

BRCA1

p.Arg1699Gln is a reduced-penetrance allele that was determined to be associated with intermediate risk; the estimated cumulative risk to age 70 for breast or ovarian cancer was 24% [Spurdle et al 2012].

BRCA2

p.Lys3326Ter was associated with a lower risk of developing breast and ovarian cancer than other BRCA2 pathogenic variants in a large case-control study based on an international consortium of individuals; for breast cancer the odds ratio (ORw) was 1.28; for invasive ovarian cancer the ORw was 1.26 [Meeks et al 2015].

An ovarian cancer cluster region (OCCR) in or near exon 11 in both BRCA1 and BRCA2 has been identified [Rebbeck et al 2015]. Pathogenic variants within the OCCR have been associated with a higher ratio of ovarian to breast cancer than is seen in families with a pathogenic variant elsewhere in the genes.

In BRCA1 and BRCA2, multiple breast cancer cluster regions have been observed and are associated with relatively elevated breast cancer risk and lower ovarian cancer risk [Rebbeck et al 2015].

Penetrance

The penetrance of breast, ovarian, and other cancers associated with pathogenic variants in BRCA1 and BRCA2 is less than 100% (see Table 2).

Prevalence

BRCA1 and BRCA2 pathogenic variants are the most common cause of HBOC. The prevalence of BRCA1 and BRCA2 pathogenic variants in the general population is estimated at 1:400 to 1:500 [Anglian Breast Cancer Study Group 2000, Whittemore et al 2004].

The prevalence of BRCA1- and BRCA2-associated HBOC is increased in certain populations due to founder variants (see Table 6):

Founder variants in BRCA1 and/or BRCA2 have also been reported in several additional populations, including individuals of African, Amish, and Icelandic ancestry (see Table 6).

Differential Diagnosis

Syndromic breast cancer. Individuals with the following cancer susceptibility syndromes have an elevated breast cancer risk. In many instances, BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) can be distinguished from these other disorders based on the constellation of tumors present in the family; however, in some cases, molecular genetic testing may be necessary to differentiate the disorders.

Table 3.

Genes Associated with Cancer Susceptibility to Consider in the Differential Diagnosis of BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Gene(s)Cancer Susceptibility SyndromeMOIAssociated Cancers / Distinctive Features
High-penetrance (high-risk) genes for breast cancer
ATMATM c.7271T>GADSpecific ATM pathogenic variants (e.g., c.7271T>G) are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer (see below). 1
CDH1 Hereditary diffuse gastric cancer ADBreast cancer (lobular), diffuse gastric cancer. Majority of cancers occur before age 40 yrs.
PALB2 PALB2-related cancer susceptibility (OMIM 620442)ADBreast cancer ≤58%, 2 ovarian cancer, male breast cancer, pancreatic cancer
PTEN PTEN hamartoma tumor syndrome ADBreast cancer. Other cancers: thyroid, renal cell carcinoma, endometrial, colorectal. Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules. Affected persons usually present by late 20s.
STK11 Peutz-Jeghers syndrome ADBreast cancer. Other cancers: GI, ovarian (mostly SCTAT), cervical (adenoma malignum), pancreatic, Sertoli cell testicular. GI polyposis, mucocutaneous pigmentation, hyperpigmented macules on fingers.
TP53 Li-Fraumeni syndrome ADBreast cancer (often premenopausal). Other cancers: soft tissue sarcoma, osteosarcoma, brain, adrenocortical carcinoma, leukemias. Early-onset & multiple primary cancers.
Moderate-penetrance (moderate-risk) genes for breast &/or ovarian cancer
ATM ATM-related cancer susceptibility (ATM heterozygotes; see Ataxia-Telangiectasia.)ADSpecific ATM pathogenic variants, most notably c.7271T>G, are assoc w/high-penetrance breast cancer; heterozygosity for most other ATM pathogenic variants is assoc w/moderate-penetrance breast cancer. ↑ risk for other types of tumors such as pancreatic cancer & prostate cancer.
BARD1 BARD1-related cancer susceptibility (OMIM 114480)ADBreast cancer
BRIP1 BRIP1-related cancer susceptibility (OMIM 605882)ADEpithelial ovarian cancer, 3 possible ↑ risk for breast cancer
CHEK2 CHEK2-related cancer susceptibility (OMIM 604373)ADBreast cancer 4
EPCAM
MLH1
MSH2
MSH6
PMS2
Lynch syndrome ADOvarian cancer, slightly ↑ risk for breast cancer. Colorectal polyps, endometrial cancer, gastric cancer, & other cancers. 5
RAD51C RAD51C-related cancer susceptibility (OMIM 613399)ADOvarian cancer, possibly breast cancer (particularly ER/PR negative breast cancer)
RAD51D RAD51D-related cancer susceptibility (OMIM 614291)ADOvarian cancer, possibly breast cancer (particularly ER/PR negative breast cancer)

AD = autosomal dominant; ER = estrogen receptor; GI = gastrointestinal; MOI = mode of inheritance; PR = progesterone receptor; SCTAT = sex cord tumor with annular tubules

1.
2.
3.
4.

The CHEK2 variant c.1100delC (NM_007194​.3) is associated with an estimated two- to threefold increased breast cancer risk in women and a tenfold increased risk in men [CHEK2 Consortium 2004, Bernstein et al 2006, Weischer et al 2007].

5.

Note regarding PMS2: Although studies have suggested a 3% lifetime risk for ovarian cancer that is higher than the observed risk in the general population, studies that specifically examine risks among individuals with PMS2 pathogenic variants have not demonstrated a statistically significant relative increased risk for ovarian cancer.

Management

Evaluations Following Initial Diagnosis

Individuals who have a germline pathogenic variant in BRCA1 or BRCA2 are counseled at the time of disclosure of molecular genetic test results about their options for Surveillance and Prevention of Primary Manifestations.

Treatment of Manifestations

Breast cancer. National Comprehensive Cancer Network (NCCN) guidelines suggest that women with a BRCA1 or BRCA2 pathogenic variant could consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer (NCCN Guidelines; no-fee registration and login required).

PARP inhibitors have emerged as a promising treatment in individuals with BRCA1- and BRCA2-associated breast cancer, given their role in DNA repair. Because BRCA1, BRCA2, and PARP participate in DNA repair, their mutual disruption could lead to "synergistic lethality" of tumor cells. PARP inhibitors were first studied in women with BRCA1- and BRCA2-associated metastatic breast cancer. Significant improvement was seen in in progression-free survival, leading to FDA approval of olaparib for women with locally advanced metastatic breast cancer in 2017 [Robson et al 2017, Litton et al 2018]. In a recent randomized, double-blind Phase III trial, olaparib also improved progression-free survival in individuals with early, high-risk, human epidermal growth factor receptor 2-negative BRCA1- and BRCA2-associated breast cancer in the adjuvant setting [Tutt et al 2021].

Ovarian cancer. PARP inhibitors were first found to improve response rates in the setting of ovarian cancer recurrence after failure of platinum-based therapies [Fong et al 2009]. Olaparib has subsequently shown significantly improved progression-free survival in platinum-sensitive recurrent ovarian cancer as maintenance therapy. In this study, individuals with BRCA1 and BRCA2 pathogenic variants showed the most benefit [Ledermann et al 2014]. Olaparib has also demonstrated significant benefit as maintenance therapy in women with newly diagnosed disease in advanced BRCA1- and BRCA2-associated ovarian cancer following primary therapy. In the SOLO-1 trial, women randomized to olaparib maintenance treatment had a 70% lower risk of disease progression or death compared to the placebo [Moore et al 2018]. Olaparib was given FDA approval for metastatic ovarian cancer in 2014, for maintenance therapy for recurrent disease in 2017, and for maintenance therapy after completion of adjuvant therapy in 2019.

Prostate cancer. After promising Phase I data on the use of olaparib in solid tumors, a Phase II study established its activity in men with BRCA1- and BRCA2-associated advanced prostate cancer [Kaufman et al 2015]. A subsequent Phase II trial compared olaparib to androgen targeted therapy plus prednisone in men with progressive prostate cancer who had pathogenic variants in DNA damage repair genes, including BRCA1 and BRCA2. A significant improvement in response rate and disease-free survival was seen in the olaparib treatment group. Both olaparib and rucaparib were approved by the FDA in 2020 for use in this setting [De Bono et al 2020].

Pancreatic cancer. The poor response of pancreatic cancer to standard systemic therapies has intensified the search for novel targeted agents. The Phase III POLO trial randomized individuals with BRCA1- and BRCA2-associated metastatic pancreatic cancer to olaparib vs placebo. Response rates were 22.1% in the olaparib group and 9.6% in the placebo group. Both progression-free survival and overall survival were doubled in the olaparib group. Toxicities, especially when a PARP inhibitor is combined with other systemic therapy, however, limit its use. The FDA has approved olaparib as maintenance therapy for BRCA1- and BRCA2-associated advanced pancreatic cancer.

Melanoma. Treatment is per dermatologist and/or oncologist.

Prevention of Primary Manifestations

Breast cancer

  • Consider prophylactic bilateral mastectomy.
  • Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
  • Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a BRCA2 germline variant [King et al 2001]. The sample size, however, was extremely small. There have been no prospective randomized trials of tamoxifen as a chemoprevention agent specifically in women with BRCA1 or BRCA2 pathogenic variants. Several studies, however, have found a significant protective effect of tamoxifen on the risk of contralateral breast cancer in women with BRCA1 or BRCA2 pathogenic variants. Risk reduction in these studies ranged from 50% to 69%. These studies are limited by their retrospective case-control designs [Gronwald et al 2006, Pierce et al 2006, Phillips et al 2013].
    Note: Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.
  • Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [Jernström et al 2004].

Ovarian cancer (including fallopian tube cancer)

  • Consider prophylactic salpingo-oophorectomy, recognizing that completion of childbearing may factor into this decision. A prospective cohort study of 2,482 women with BRCA1 or BRCA2 pathogenic variants reported a 79% reduction in ovarian cancer mortality and a 60% reduction on all-cause mortality associated with risk-reducing oophorectomy [Marchetti et al 2014].
  • With the realization that the fallopian tube is frequently the site of serous ovarian cancer and its precursor lesions, a new paradigm of prophylactic salpingectomy after childbearing followed by delayed oophorectomy at the time of menopause has been suggested. While theoretically offering protection against ovarian cancer, this approach would also avoid the adverse consequences of premature menopause. Currently studies are under way to determine its feasibility, safety, and efficacy [Swanson & Bakkum-Gamez 2016].
  • Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [Cibula et al 2011]. In a meta-analysis of modifiers of risk of cancer in individuals with pathogenic variants in BRCA1 or BRCA2, tubal ligation was associated with a reduced risk of ovarian cancer in females with a BRCA1 pathogenic variant, although study design issues limit the impact of these findings [Friebel et al 2014].
  • A meta-analysis of 18 studies including 13,677 women with BRCA1 or BRCA2 pathogenic variants found a 50% reduction in risk of ovarian cancer associated with oral contraceptive use [Iodice et al 2010]. The maximum benefit of oral contraceptives is obtained with three to six years of use [Kotsopoulos et al 2015].
    Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline BRCA1 or BRCA2 pathogenic variant.

Surveillance

Table 4.

Recommended Surveillance for Women with BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

System/ConcernEvaluationFrequency
Breast cancer Breast self-examMonthly
Clinical breast examEvery 6-12 mos beginning at age 25 yrs
MammogramAnnually beginning at age 30 yrs
Breast MRIAnnually beginning at age 25 yrs or earlier if breast cancer was diagnosed in family member < age 30 yrs
Ovarian cancer Screening not recommended 1
Melanoma Skin exam w/dermatologistIndividualized based on family history
Pancreatic
cancer
In asymptomatic persons who meet criteria based on mutation status & family history, contrast-enhanced MRI/MRCP &/or EUS may be considered in a research setting to better delineate the risks & benefits of pancreatic cancer screening.

EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography

1.

For women who have not elected to undergo prophylactic bilateral salpingo-oophorectomy: while some clinicians conduct annual transvaginal ultrasound and/or CA-125 concentration, these modalities have not been effective in detecting early-stage ovarian cancer, either in high-risk or in average-risk women.

Table 5.

Recommended Surveillance for Men with BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

System/ConcernEvaluationFrequency
Breast cancer Breast self-exam trainingAt the time of identification of a BRCA1 or BRCA2 pathogenic variant
Breast self-examMonthly beginning at age 35 yrs
Clinical breast examAnnually beginning at age 35 yrs
Prostate cancer Serum PSA; digital rectal examAnnually beginning at age 40 yrs
Melanoma Skin exam w/dermatologistIndividualized based on family history
Pancreatic
cancer
In asymptomatic persons who meet criteria based on mutation status & family history, contrast-enhanced MRI/MRCP &/or EUS may be considered in a research setting to better delineate the risks & benefits of pancreatic cancer screening.

EUS = endoscopic ultrasound; MRCP = magnetic resonance cholangiopancreatography

Agents/Circumstances to Avoid

No data specific to individuals with BRCA1 or BRCA2 pathogenic variants are available.

Evaluation of Relatives at Risk

Once a cancer-predisposing BRCA1 or BRCA2 germline variant has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial variant and thus need increased surveillance and specific treatments when a cancer is identified.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several ongoing studies are investigating novel approaches to the treatment of BRCA1- and BRCA2-associated breast and ovarian cancer. The majority of these studies involve PARP inhibitors.

Several prospective and randomized clinical trials are investigating PARP inhibitor treatment of metastatic pancreatic cancer [Chi et al 2021, Macchini et al 2021].

Studies to identify biomarkers of disease resistance and expected treatment toxicity are also under way [Jeong & Park 2021].

Additional clinical trials are exploring the use of other PARP inhibitors alone or in combination with other systemic treatments.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

Other

Hormone replacement therapy (HRT). General population studies suggest that long-term estrogen replacement therapy in postmenopausal women may increase breast cancer risk, but that short-term use to treat menopausal symptoms does not. However, even relatively short-term combined estrogen plus progestin use was shown to increase the incidence of breast cancers in a randomized, placebo-controlled trial of HRT [Chlebowski et al 2003].

Three observational studies on the impact of HRT on breast cancer risk in BRCA 1 and BRCA2 heterozygotes have been published. Rebbeck et al [2005] evaluated breast cancer risk associated with HRT after bilateral prophylactic oophorectomy in a cohort of 462 women with a BRCA1 or BRCA2 germline pathogenic variant and found that HRT of any type after bilateral prophylactic oophorectomy did not significantly alter the reduction in breast cancer risk associated with the surgery. The postoperative follow up was 3.6 years. It was concluded that short-term HRT does not substantially increase the risk for breast cancer in women with a BRCA1 or BRCA2 germline pathogenic variant. A subsequent study of expanded data from this cohort included 1,299 women with a mean follow up of 5.4 years. There was no increase in breast cancer risk, and a significant decrease in breast cancer risk was found among BRCA1 heterozygotes [Domchek et al 2011]. In another matched case-control study of 472 postmenopausal women with a BRCA1 pathogenic variant, the use of HRT was associated with a reduction in breast cancer risk [Eisen et al 2008]. Finally, a case-control study of 432 matched pairs with a mean follow up of 4.3 years also found a decrease in the risk for breast cancer in BRCA1 heterozygotes [Kotsopoulos et al 2016]. Taken together, these studies support the short-term use of HRT among BRCA1 and BRCA2 heterozygotes who have undergone surgical menopause.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband with a BRCA1 or BRCA2 pathogenic variant

  • The vast majority of individuals with a germline pathogenic variant in BRCA1 or BRCA2 inherited it from a parent. The parent with the pathogenic variant may or may not have had a cancer diagnosis depending on the following variables:
    • Penetrance of the variant
    • Sex of the parent
    • Age of the parent
    • Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
    • Early death of the parent
  • It is appropriate to offer molecular genetic testing to both parents of an individual with a BRCA1 or BRCA2 germline pathogenic variant to determine which side of the family is at risk. Generally, the pattern of cancers seen in the family guides which parent is tested first.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • The proband has a de novo pathogenic variant. De novo variants have been rarely reported (≤5%) [Golmard et al 2016, Antonucci et al 2017].
    • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [Alhopuro et al 2020]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
  • An apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the BRCA1 or BRCA2 pathogenic variant identified in the proband.

Sibs of a proband with a BRCA1 or BRCA2 pathogenic variant. The risk to full sibs of the proband depends on the genetic status of the proband's parents:

  • If one parent has the BRCA1 or BRCA2 germline pathogenic variant identified in the proband, the risk that a sib will inherit the pathogenic variant is 50%.
  • The risk of developing cancer in a sib who inherits the familial BRCA1 or BRCA2 pathogenic variant depends on numerous variables including the penetrance of the pathogenic variant and the sex and age of the heterozygous sib.

Offspring of a proband with a BRCA1 or BRCA2 pathogenic variant

  • The offspring of an individual identified as having a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the pathogenic variant.
  • The risk of developing cancer in offspring who inherit the BRCA1 or BRCA2 pathogenic variant depends on numerous variables including the penetrance of the pathogenic variant and the sex and age of the heterozygous individual.

Other family members of a proband with a BRCA1 or BRCA2 pathogenic variant. The risk to other family members depends on the genetic status of the proband's parents. If a parent has a BRCA1 or BRCA2 germline pathogenic variant, the parent's family members are at risk. Their exact risk depends on their biological relationship with the proband.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for the determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

At-risk asymptomatic adult relatives. In general, relatives of an individual who has a BRCA1 or BRCA2 germline pathogenic variant should be counseled regarding their risk of having inherited the same variant, their options for molecular genetic testing, their cancer risk, and recommendations for cancer screening (see Surveillance) and prophylactic surgery (see Prevention of Primary Manifestations).

At-risk adult relatives who have not inherited the cancer-predisposing germline variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on personal risk factors. For example, a female at-risk relative who does not have the family-specific BRCA1 or BRCA2 pathogenic variant may still be at an elevated risk for breast cancer based on a breast biopsy history that revealed atypical ductal hyperplasia.

For family members determined to be at general population risk of developing cancer, appropriate cancer screening such as that recommended by the American Cancer Society or the National Comprehensive Cancer Network (NCCN) for individuals of average risk is recommended. Note: This presumption cannot apply to individuals who did not have an identifiable BRCA1 or BRCA2 germline pathogenic variant if the affected individual in the family either has not undergone molecular genetic testing of BRCA1 or BRCA2 or did not have an identified BRCA1 or BRCA2 pathogenic variant.

Testing of asymptomatic individuals younger than age 18 years. In general, genetic testing for BRCA1- and BRCA2-associated HBOC is not recommended for at-risk individuals younger than age 18 years. Guidelines established jointly by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should only be performed in individuals younger than age 18 years when it will affect their medical management. Surveillance for BRCA1- and BRCA2-associated HBOC is typically recommended to begin at approximately age 25, which is why it is recommended that the decision to test be postponed until an individual reaches adulthood and can make an independent decision. It is important to note, however, that since there are rare reports of individuals with BRCA1- and BRCA2-associated HBOC diagnosed with cancer at very young ages, it is recommended that screening be individualized based on the earliest diagnosis in the family.

For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Prenatal Testing and Preimplantation Genetic Testing

Once the BRCA1 or BRCA2 germline pathogenic variant has been identified in the family, prenatal and preimplantation genetic testing for BRCA1- and BRCA2-associated HBOC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors Position Statement on prenatal testing in adult-onset conditions.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Breast Cancer Information Core
    Breast cancer resources
    National Human Genome Research Institute (NHGRI)
  • Bright Pink
    670 North Clark Street
    Suite 2
    Chicago IL 60654
  • FORCE: Facing Our Risk of Cancer Empowered
    A discussion forum specifically for women who are at a high risk of developing ovarian cancer or breast cancer
    16057 Tampa Palms Boulevard West
    PMB #373
    Tampa FL 33647
    Phone: 866-288-7475 (toll-free)
    Fax: 954-827-2200
    Email: info@facingourrisk.org
  • Gilda's Club Worldwide
    48 Wall Street
    11th Floor
    New York NY 10005
    Phone: 888-445-3248 (toll-free)
    Fax: 917-305-0549
    Email: info@gildasclub.org
  • National Breast Cancer Coalition (NBCC)
    Phone: 800-622-2838
    Fax: 202-314-3458
    Email: info@stopbreastcancer.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Cancer Institute (NCI)
    Phone: 800-4-CANCER
    Email: NCIinfo@nih.gov
  • National Ovarian Cancer Coalition (NOCC)
    2501 Oak Lawn Avenue
    Suite 435
    Dallas TX 75219
    Phone: 888-682-7426 (Toll-free Helpline); 214-273-4200
    Fax: 214-273-4201
    Email: nocc@ovarian.org
  • NCBI Genes and Disease
  • Probability of Breast Cancer in American Women
    National Cancer Institute Public Inquiries Office
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • Sharsheret
    Phone: 866-474-2774
    Email: info@sharsheret.org
  • Susan G. Komen Breast Cancer Foundation
    Phone: 877 GO KOMEN
    Email: helpline@komen.org
  • American Cancer Society
    Phone: 800-227-2345
  • CancerCare
    Phone: 800-813-4673
    Email: info@cancercare.org
  • National Cancer Institute (NCI)
    Phone: 800-422-6237
    Email: NCIinfo@nih.gov
  • National Coalition for Cancer Survivorship (NCCS)
    Phone: 877-NCCS-YES
    Email: info@canceradvocacy.org
  • Familial Ovarian Cancer Registry
    Roswell Park Cancer Institute
    Elm and Carlton Streets
    Buffalo NY 14263
    Phone: 716-845-4503

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer (View All in OMIM)

113705BRCA1 DNA REPAIR-ASSOCIATED PROTEIN; BRCA1
114480BREAST CANCER
600185BRCA2 DNA REPAIR-ASSOCIATED PROTEIN; BRCA2
604370BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
612555BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2; BROVCA2
613347PANCREATIC CANCER, SUSCEPTIBILITY TO, 2
614320PANCREATIC CANCER, SUSCEPTIBILITY TO, 4; PNCA4

Molecular Pathogenesis

BRCA1 encodes breast cancer type 1 susceptibility protein (BRCA1), a phosphoprotein normally located in the nucleus [Chen et al 1996]. BRCA1 interacts with several proteins involved in cellular pathways, including cell-cycle progression, gene transcription regulation, DNA damage response, and ubiquitination [Deng 2006, Rosen et al 2006].

The BRCA1/BARD1 protein complex enhances ubiquitin ligase activity, which is associated with the regulation of centrosome function and involved in DNA repair and cell cycle regulation [Bork et al 1997, Callebaut & Mornon 1997, Sankaran et al 2006].

BRCA1 colocalizes with BRCA2 and RAD51 at sites of DNA damage and activates RAD51-mediated homologous recombination repair of DNA double-strand breaks [Cousineau et al 2005]. BRCA2 regulates the availability and activity of RAD51, which coats single-strand DNA to form a nucleoprotein filament that invades and pairs with a homologous DNA duplex to initiate strand exchange [Venkitaraman 2002].

Mechanism of disease causation. Loss of function

Table 6.

BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer: Notable Pathogenic Variants by Gene

GeneReference SequencesDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeComment [Reference]
BRCA1 NM_007294​.4
NP_009225​.1
c.68_69delAG
(185delAG or 187delAG)
p.Glu23ValfsTer17Founder variant in Ashkenazi Jews; accounts for 72% of pathogenic variants in this population 2
c.115T>Gp.Cys39GlyFounder variant in Inuit from Ammassalik; accounts for >95% of pathogenic variants in this population 3
c.815_824dupAGCCATGTGG
(943ins10)
p.Thr276AlafsTer14Founder variant in those of West African ancestry 4
c.5096G>Ap.Arg1699GlnIntermediate risk variant 5
c.5266dupC
(5385insC or 5382insC)
p.Gln1756ProfsTer74Founder variant in Ashkenazi Jews; accounts for 26% of pathogenic variants in this population 2
BRCA2 NM_000059​.4
NP_000050​.3
c.771_775delTCAAA (999del5)p.Asn257LysfsTer17Founder variant in Icelanders 6
c.5073dupAp.Trp1692MetfsTer3Founder variant in Amish of Somerset County, Pennsylvania 7
c.5946delT
(6174delT)
p.Ser1982ArgfsTer22Founder variant in Ashkenazi Jews; accounts for 95% of pathogenic variants in this population 2

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.
3.
4.
5.
6.
7.

Chapter Notes

Author History

Julie O Bars Culver, MS; Fred Hutchinson Cancer Research Center (1998-2011)
Wylie Burke, MD, PhD; University of Washington (1998-2005)
Mary B Daly, MD, PhD (1998-present)
Gerald L Feldman, MD, PhD; Wayne State University School of Medicine (2002-2016)
Judith L Hull, MS; Memorial Sloan-Kettering Cancer Center (1998-2005)
Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center (1998-2007)
Tuya Pal, MD (2016-present)
Nancie Petrucelli, MS (2002-present)

Revision History

  • 21 September 2023 (np,sw) Revision: information about cancer risk in individuals who are heterozygous for a pathogenic variant in ATM added to Differential Diagnosis
  • 26 May 2022 (mbd,tp) Revision: recommended surveillance for ovarian and pancreatic cancer (Tables 4 and 5)
  • 3 February 2022 (sw) Comprehensive update posted live
  • 15 December 2016 (sw) Comprehensive update posted live
  • 26 September 2013 (me) Comprehensive update posted live
  • 20 January 2011 (me) Comprehensive update posted live
  • 19 June 2007 (me) Comprehensive update posted live
  • 5 December 2005 (cd) Revision: Differential Diagnosis
  • 3 September 2004 (jbc) Revision: Genetically Related Disorders
  • 29 March 2004 (ca) Comprehensive update posted live
  • 4 March 2000 (me) Comprehensive update posted live
  • 4 September 1998 (pb) Review posted live
  • January 1998 (jbc) Original submission

References

Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 8-25-23.
  • National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Cancer. Available online; no-fee registration and login required. Accessed 8-25-23.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 8-25-23.
  • Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, Lipkin SM, Syngal S, Wollins DS, Lindor NM. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33:3660-7. [PubMed]

Literature Cited

  • Alhopuro P, Vainionpää R, Anttonen AK, Aittomäki K, Nevanlinna H, Pöyhönen M. Constitutional mosaicism for a BRCA2 mutation as a cause of early-onset breast cancer. Fam Cancer. 2020;19:307-10. [PMC free article: PMC7497290] [PubMed: 32468491]
  • Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012;30:2654-63. [PMC free article: PMC3413277] [PubMed: 22711857]
  • Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer. 2000; 83:1301-8. [PMC free article: PMC2408797] [PubMed: 11044354]
  • Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, Lee A, Subramanian D, De Leeneer K, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomäki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, Andrulis IL, Radice P, Tondini C, Manoukian S, Toland AE, Miron P, Weitzel JN, Domchek SM, Poppe B, Claes KB, Yannoukakos D, Concannon P, Bernstein JL, James PA, Easton DF, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King MC, Couch FJ, Southey MC, Winqvist R, Foulkes WD, Tischkowitz M. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497-506. [PMC free article: PMC4157599] [PubMed: 25099575]
  • Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjäkoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-30. [PMC free article: PMC1180265] [PubMed: 12677558]
  • Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580-90. [PMC free article: PMC2409934] [PubMed: 15381934]
  • Antonucci I, Provenzano M, Sorino L, Rodrigues M, Palka G, Stuppia L. A new case of "de novo" BRCA1 mutation in a patient with early-onset breast cancer. Clin Case Rep. 2017;5:238-40. [PMC free article: PMC5331191] [PubMed: 28265380]
  • Bahar AY, Taylor PJ, Andrews L, Proos A, Burnett L, Tucker K, Friedlander M, Buckley MF. The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data. Cancer. 2001;92:440-5. [PubMed: 11466700]
  • Basu NN, Ingham S, Hodson J, Lalloo F, Bulman M, Howell A, Evans DG. Risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a 30-year semi-prospective analysis. Fam Cancer. 2015;14: 531-8. [PubMed: 26239694]
  • Bernstein JL, Teraoka SN, John EM, Andrulis IL, Knight JA, Lapinski R, Olson ER, Wolitzer AL, Seminara D, Whittemore AS, Concannon P. The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the breast cancer family registry. Cancer Epidemiol Biomarkers Prev. 2006;15:348-52 [PubMed: 16492927]
  • Bolton KL, Chenevix-Trench G, Gob C, Sadetzke S, Ramus SJ, Karlan BY, Lambrechts D, Despierre E, Barrowdale D, McGuffog L, Healey S, Easton DF, Sinilnikova O, Benetiz J, Garcia MJ, Neuhausen S, Gail MH, Hartge P, Peock S, Frost D, Evans DG, Eeles R, Godwin AK, Daly MB, Kwong A, Ma EDK, Lazaro C, Blanco I, Montagna M, D'Andrea E, Nicoletto MO, Johnatty SF, Jjaer SK, Jensen A, Hogdall E, Goode EL, Fridley BL, Loud JT, Greene MH, Mai PL, Chetrit A, Lubin F, Hirsh-Yechezkel G, Glendon G, Andrulis IL, Toland AE, Senter L, Gore ME, Gourley C, Michie CO, Song H, Tyrer J, Whittemore AS, McGuire V, Sieh W, Kristoffersson U, Olsson H, Borg A, Levine DA, Steele L, Beattie MS, Chan S, Nussbaum RL, Moysich KB, Gross J, Cass I, Walsh C, Li AJ, Leuchter R, Gordon O, Garcia-Closas M, Gayther SA, Chanock SJ, Antoniou AC, Pharoah PDP, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 2012;307:382-90. [PMC free article: PMC3727895] [PubMed: 22274685]
  • Bordeleau L, Panchal S, Goodwin P. Prognosis of BRCA-associated breast cancer: a summary of evidence. Breast Cancer Res Treat. 2010;119:13-24. [PubMed: 19789974]
  • Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF, Koonin EV. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 1997;11:68-76 [PubMed: 9034168]
  • Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310-6 [PubMed: 10433620]
  • Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94:1365-72. [PubMed: 12237282]
  • Callebaut I, Mornon JP. From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett. 1997;400:25-30 [PubMed: 9000507]
  • Casey MJ, Synder C, Bewtra C, Narod SA, Watson P, Lynch HT. Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecol Oncol. 2005;97:457-67 [PubMed: 15863145]
  • CHEK2 Consortium. CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 2004;74:1175-82. [PMC free article: PMC1182081] [PubMed: 15122511]
  • Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863-71. [PMC free article: PMC2323978] [PubMed: 16484695]
  • Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329-33. [PMC free article: PMC2267287] [PubMed: 17416853]
  • Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH. BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. 1996;56:3168-72. [PubMed: 8764100]
  • Chi J, Chung SY, Parakrama R, Fayyaz F, Jose J, Saif MW. The role of PARP inhibitors in BRCA mutated pancreatic cancer. Therap Adv Gastroenterol. 2021;14:17562848211014818. [PMC free article: PMC8120537] [PubMed: 34025781]
  • Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003; 289:3243-53 [PubMed: 12824205]
  • Cibula D, Widschwendter M, Majek O, Dusek L. Tubal ligation and the risk of ovarian cancer: review and meta-analysis. Hum Reprod Update. 2011;17:55-67. [PubMed: 20634209]
  • Cousineau I, Abaji C, Belmaaza A. BRCA1 regulates RAD51 function in response to DNA damage and suppresses spontaneous sister chromatid replication slippage: implications for sister chromatid cohesion, genome stability, and carcinogenesis. Cancer Res. 2005;65:11384-91 [PubMed: 16357146]
  • Cox DM, Nelson KL, Clytone M, Collins DL. Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations. Mol Genet Genomic Med. 2018;6:1236-42. [PMC free article: PMC6305650] [PubMed: 30152102]
  • Dagan E. Predominant Ashkenazi BRCA1/2 mutations in families with pancreatic cancer. Genet Test. 2008;12:267-71. [PubMed: 18439109]
  • Daly MB, Dresher CW, Yates MS, Jeter JM, Karlan BY, Alberts DS, Lu KH. Salpingectomy as a means to reduce ovarian cancer risk. Cancer Prev Res (Phila). 2015;8:342-8. [PMC free article: PMC4417454] [PubMed: 25586903]
  • Dann RB, DeLoia JA, Timms KM, Zorn KK, Potter J, Flake DD, Lanchbury JS, Kirvak TC. BRCA1/2 muatations and expression: resonse to platinum chemogherapy in patients with advanced stage epithelial ovarian cancer. Gynecol Oncol. 2012;125:677-82. [PubMed: 22406760]
  • De Bono J, Mateo J, Fuzazi K, Saad F, Shore N, Sandhu S, Chi KN, Sartor O, Agarwal N, Olmos D, Thiery-Vuillemin A, Twardowski P, Mehra N, Goessl C, Kang J, Burgents J, Wu W, Kohlmann A, Adelman CA, Hussain M. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382:2091-102. [PubMed: 32343890]
  • de Jonge MM, Mooyaart AL, Vreeswijk MP, de Kroon CD, van Wezel T, van Asperen CJ, Smit VT, Dekkers OM, Bosse T. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: a meta-analysis and case report. Eur J Cancer. 2017;72:215-25. [PubMed: 28049106]
  • de la Hoya M, Díez O, Pérez-Segura P, Godino J, Fernández JM, Sanz J, Alonso C, Baiget M, Díaz-Rubio E, Caldés T. Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics. J Med Genet. 2003;40:503-10. [PMC free article: PMC1735524] [PubMed: 12843322]
  • Deng CX. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Research. 2006;34:1416-26 [PMC free article: PMC1390683] [PubMed: 16522651]
  • Domchek SM, Friebel T, Neuhausen SL, Lynch HT, Singer CF, Eeles RA, Isaacs C, Tung NM, Ganz PA, Couch FJ, Weitzel JN, Olopade OI, Rubinstein WS, Tomlinson GE, Pichert GC, Daly MB, Matloff ET, Evans DG, Garber JE, Rebbeck TR, et al. Is hormone replacement therapy (HRT) following risk-reducing salpingo-oophorectomy (RRSO) in BRCA1 (B1)- and BRCA2 (B2)-mutation carriers associated with an increased risk of breast cancer. Abstract 1501. Chicago, IL: ASCO Annual Meeting; 2011.
  • Eisen A, Lubinski J, Gronwald J, Moller P, Lynch HT, Klijn J, Kim-Sing C, Neuhausen SL, Gilbert L, Ghadirian P, Manoukian S, Rennert G, Friedman E, Isaacs C, Rosen E, Rosen B, Daly M, Sun P, Narod SA, et al. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008;100:1361-7. [PMC free article: PMC2556701] [PubMed: 18812548]
  • Euhus DM, Smith KC, Robinson L, Stucky A, Olopade OI, Cummings S, Garber JE, Chittenden A, Mills GB, Rieger P, Esserman L, Crawford B, Hughes KS, Roche CA, Ganz PA, Seldon J, Fabian CJ, Klemp J, Tomlinson G. Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst. 2002;94:844-51. [PubMed: 12048272]
  • Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, Shenton A, Howell A, Lalloo F. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474-80. [PMC free article: PMC1735807] [PubMed: 15173236]
  • Evans DG, Susnerwala I, Dawson J, Woodward E, Maher ER, Lalloo F. Risk of breast cancer in male BRCA2 carriers. J Med Genet. 2010;47:710-1. [PubMed: 20587410]
  • Ferla R, Calò V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 18 Suppl. 2007;6:vi93-8. [PubMed: 17591843]
  • Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-34. [PubMed: 19553641]
  • Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480-90 [PubMed: 11896095]
  • Friebel TM, Domchek SM, Rebbeck TR. Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst. 2014;106:dju091. [PMC free article: PMC4081625] [PubMed: 24824314]
  • Fujiwara M, McGuire VA, Felberg A, Sieh W, Whittemore AS, Longacre TA. Prediction of BRCA1 germline mutation status in women with ovarian cancer using morphology-based criteria, identification of a BRCA1 ovarian cancer phenotype. Am J Surg Pathol. 2012;36:1170-7. [PMC free article: PMC3422129] [PubMed: 22790858]
  • Gabai-Kapara E, Lahad A, Kaufman B, Friedman E, Segev S, Renbaum P, Beeri R, Gal M, Grinshpun-Cohen J, Djemal K, Mandell JB, Lee MK, Beller U, Catane R, King MC, Levy-Lahad E. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111:14205-10. [PMC free article: PMC4191771] [PubMed: 25192939]
  • Gallagher DJ, Gaudet MM, Pal P, Kirchhoff T, Balistreri L, Vora K, Bhatia J, Stadler Z, Fine SW, Reuter V, Zelefsky M, Morris MJ, Scher HI, Klein RJ, Norton L, Eastham JA, Scardino PT, Robson ME, Offit K. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16:2115-21. [PMC free article: PMC3713614] [PubMed: 20215531]
  • Golan T, Kanji ZS, Epelbaum R, Devaud N, Dagan E, Holter S, Aderka D, Paluch-Shimon S, Kaufman B, Gershoni-Baruch R, Hedley D, Moore MJ, Friedman E, Gallinger S. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br J Cancer. 2014;111:1132-8. [PMC free article: PMC4453851] [PubMed: 25072261]
  • Golmard L, Delnatte C, Laugé A, Moncoutier V, Lefol C, Abidallah K, Tenreiro H, Copigny F, Giraudeau M, Guy C, Barbaroux C, Amorim G, Briaux A, Guibert V, Tarabeux J, Caputo S, Collet A, Gesta P, Ingster O, Stern MH, Rouleau E, de Pauw A, Gauthier-Villars M, Buecher B, Bézieau S, Stoppa-Lyonnet D, Houdayer C. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. Oncogene. 2016;35:1324-7. [PubMed: 26028024]
  • Graeser MK, Engel C, Rhiem K, Gadzicki D, Bick U, Kast K, Froster UG, Schlehe B, Bechtold A, Arnold N, Preisler-Adams S, Nestle-Kraemling C, Zaino M, Loeffler M, Kiechle M, Meindl A, Varga D, Schmutzler RK. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2009;27:5887-92. [PubMed: 19858402]
  • Gronwald J, Tung N, Foulkes WD, Offit K, Gershoni R, Daly M, Kim-Sing C, Olsson H, Ainsworth P, Eisen A, Saal H, Friedman E, Olopade O, Osborne M, Weitzel J, Lynch H, Ghadirian P, Lubinski J, Sun P, Narod SA, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer. 2006;118:2281-4. [PubMed: 16331614]
  • Gumaste PV, Penn LA, Cymerman RM, Kirchhoff T, Polsky D, McLellan B. Skin cancer risk in BRCA1/2 mutation carriers. Br J Dermatol. 2015;172:1498-506. [PMC free article: PMC5785081] [PubMed: 25524463]
  • Haffty BG, Harrold E, Khan AJ, Pathare P, Smith TE, Turner BC, Glazer PM, Ward B, Carter D, Matloff E, Bale AE, Alvarez-Franco M. Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet. 2002;359:1471-7. [PubMed: 11988246]
  • Hansen TV, Ejlertsen B, Albrechtsen A, Bergsten E, Bjerregaard P, Hansen T, Myrhøj T, Nielsen PB, Timmermans-Wielenga V, Andersen MK, Jønson L, Nielsen FC. A common Greenlandic Inuit BRCA1 RING domain founder mutation. Breast Cancer Res Treat. 2009;115:69-76. [PubMed: 18500671]
  • Hansen TV, Jønson L, Albrechtsen A, Steffensen AY, Bergsten E, Myrhøj T, Ejlertsen B, Nielsen FC. Identification of a novel BRCA1 nucleotide 4803delCC/c.4684delCC mutation and a nucleotide 249T>A/c.130T>A (p.Cys44Ser) mutation in two Greenlandic Inuit families: implications for genetic screening of Greenlandic Inuit families with high risk for breast and/or ovarian cancer. Breast Cancer Res Treat. 2010;124:259-64. [PubMed: 20437199]
  • Harboe TL, Eiberg H, Kern P, Ejlertsen B, Nedergaard L, Timmermans-Wielenga V, Nielsen IM, Bisgaard ML. A high frequent BRCA1 founder mutation identified in the Greenlandic population. Fam Cancer. 2009;8:413-9. [PubMed: 19504351]
  • Hearle N, Damato BE, Humphreys J, Wixey J, Green H, Stone J, Easton DF, Houlston RS. Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44:458-62. [PubMed: 12556369]
  • Ibrahim M, Yadav S, Ogunleye F, Zakalik D. Male BRCA mutation carriers: clinical characteristics and cancer spectrum. BMC Cancer. 2018;18:179. [PMC free article: PMC5809938] [PubMed: 29433453]
  • Iodice S, Barile M, Rotmensz N, Feroce I, Bonanni B, Radice P, Bernard L, Maisonneuve P, Gandini S. Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: a meta-analysis. Eur J Cancer. 2010;46: 2275-84. [PubMed: 20537530]
  • Iqbal J, Ragone A, Lubinski J, Lynch HT, Moller P, Ghadirian P, Foulkes WD, Armel S, Eisen A, Neuhausen SL, Senter L, Singer CF, Ainsworth P, Kim-Sing C, Tung N, Friedman E, Llacuachaqui M, Ping S, Narod SA, et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2012;107:2005-9. [PMC free article: PMC3516682] [PubMed: 23099806]
  • Jeong KY, Park MH. The significance of targeting poly (ADP-ribose) polymerase-1 in pancreatic cancer for providing a new therapeutic paradigm. Int J Mol Sci. 2021;22:3509-24. [PMC free article: PMC8037971] [PubMed: 33805293]
  • Jernström H, Lubinski J, Lynch HT, Ghadirian P, Neuhausen S, Isaacs C, Weber BL, Horsman D, Rosen B, Foulkes WD, Friedman E, Gershoni-Baruch R, Ainsworth P, Daly M, Garber J, Olsson H, Sun P, Narod SA. Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2004;96:1094-8 [PubMed: 15265971]
  • Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-50. [PMC free article: PMC6057749] [PubMed: 25366685]
  • King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, Tait J, Ford L, Dunn BK, Costantino J, Wickerham L, Wolmark N, Fisher B, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251-6 [PubMed: 11710890]
  • Kirova YM, Stoppa-Lyonnet D, Savignoni A, Sigal-Zafrani B, Fabre N, Fourquet A, et al. Risk of breast cancer recurrence and contralateral breast cancer in relation to BRCA1 and BRCA2 mutation status following breast-conserving surgery and radiotherapy. Eur J Cancer. 2005;41:2304-11. [PubMed: 16140006]
  • Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N, Guy M, Edwards S, O'Brien L, Sawyer E, Hall A, Wilkinson R, Dadaev T, Goh C, Easton D; UKGPCS Collaborators, Goldgar D, Eeles R. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105:1230-4. [PMC free article: PMC3208504] [PubMed: 21952622]
  • Kotsopoulos J, Huzarski T, Gronwald J, Moller P, Lynch HT, Neuhausen SL, Senter L, Demsky R, Foulkes WD, Eng C, Karlan B, Tung N, Singer CF, Sun P, Lubinski J, Narod SA. Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study. Breast Cancer Res Treat. 2016;155:365-73. [PubMed: 26780555]
  • Kotsopoulos J, Lubinski J, Gronwald J, Cybulski C, Demsky R, Neuhausen SL, Kim-Sing C, Tung N, Friedman S, Senter L, Weitzel J, Karlan B, Moller P, Sun P, Narod SA, et al. Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Int J Cancer. 2015;137:1136-46. [PMC free article: PMC4458227] [PubMed: 25482078]
  • Kowalewski A, Szylberg Ł, Saganek M, Napiontek W, Antosik P, Grzanka D. Emerging strategies in BRCA-positive pancreatic cancer. J Cancer Res Clin Oncol. 2018;144:1503-7. [PMC free article: PMC6061050] [PubMed: 29777302]
  • Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, Jervis S, van Leeuwen FE, Milne RL, Andrieu N, Goldgar DE, Terry MB, Rookus MA, Easton DF, Antoniou AC, McGuffog L, Evans DG, Barrowdale D, Frost D, Adlard J, Ong KR, Izatt L, Tischkowitz M, Eeles R, Davidson R, Hodgson S, Ellis S, Nogues C, Lasset C, Stoppa-Lyonnet D, Fricker JP, Faivre L, Berthet P, Hooning MJ, van der Kolk LE, Kets CM, Adank MA, John EM, Chung WK, Andrulis IL, Southey M, Daly MB, Buys SS, Osorio A, Engel C, Kast K, Schmutzler RK, Caldes T, Jakubowska A, Simard J, Friedlander ML, McLachlan SA, Machackova E, Foretova L, Tan YY, Singer CF, Olah E, Gerdes AM, Arver B, Olsson H, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402-16. [PubMed: 28632866]
  • LaDuca H, Polley EC, Yussuf A, Hoang L, Gutierrez S, Hart SN, Yadav S, Hu C, Na J, Goldgar DE, Fulk K, Smith LP, Horton C, Profato J, Pesaran T, Gau CL, Pronold M, Davis BT, Chao EC, Couch FJ, Dolinsky JS. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med. 2020;22:407-15. [PMC free article: PMC7000322] [PubMed: 31406321]
  • Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852-61. [PubMed: 24882434]
  • Lee E, McKean-Cowdin R, Ma H, Spicer DV, Van Den Berg D, Bernstein L, Ursin G. Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women. J Clin Oncol. 2011;29:4373-80. [PMC free article: PMC3221522] [PubMed: 22010008]
  • Leongamornlert D, Mahmud N, Tymrakiewicz M, Saunders E, Dadaev T, Castro E, Goh C, Govindasami K, Guy M, O'Brien L, Sawyer E, Hall A, Wilkinson R, Easton D, Goldgar D, Eeles R, Kote-Jarai Z, et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012;106:1697-701. [PMC free article: PMC3349179] [PubMed: 22516946]
  • Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im YH, Quek RGW, Markova D, Tudor IC, Hannah AL, Eiermann W, Blum JL. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753-63. [PMC free article: PMC10600918] [PubMed: 30110579]
  • Liu J, Cristea MC, Frankel P, Neuhausen SL, Steele L, Engelstaedter V, Matulonis U, Sand S, Tung N, Garber JE, Weitzel JN. Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival. Cancer Genet. 2012;205: 34-41. [PMC free article: PMC3337330] [PubMed: 22429596]
  • Macchini M, Centonze F, Peretti U, Orsi G, Militello AM, Valente MM, Cascinu S, Reni M. Treatment opportunities and future perspectives for pancreatic cancer patients with germline BRCA1-2 pathogenic variants. Cancer Treat Rev. 2021;100:102262. [PubMed: 34418781]
  • Malone KE, Begg CB, Haile RW, Borg A, Concannon P, Tellhed L, Xue S, Teraoka S, Bernstein L, Capanu M, Reiner AS, Riedel ER, Thomas DC, Mellemkjaer L, Lynch C, Boice JD, Anton-Culver H, Bernstein JL. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J Clin Oncol. 2010;28:2404-10. [PMC free article: PMC2881721] [PubMed: 20368571]
  • Marchetti C, De Felice F, Palaia I, Perniola G, Musella A, Musio D, Muzii L, Tombolini V, Panici PB. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. 2014;14:150. [PMC free article: PMC4271468] [PubMed: 25494812]
  • Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, Ramus SJ, Spurdle A, Robson M, Sherman M, Mulligan AM, Couch FJ, Engel C, McGuffog L, Healey S, Sinilnikova OM, Southey MC, Terry MB, Goldgar D, O'Malley F, John EM, Janavicius R, Tihomirova L, Hansen TV, Nielsen FC, Osorio A, Stavropoulou A, Benítez J, Manoukian S, Peissel B, Barile M, Volorio S, Pasini B, Dolcetti R, Putignano AL, Ottini L, Radice P, Hamann U, Rashid MU, Hogervorst FB, Kriege M, van der Luijt RB, Peock S, Frost D, Evans DG, Brewer C, Walker L, Rogers MT, Side LE, Houghton C, Weaver J, Godwin AK, Schmutzler RK, Wappenschmidt B, Meindl A, Kast K, Arnold N, Niederacher D, Sutter C, Deissler H, Gadzicki D, Preisler-Adams S, Varon-Mateeva R, Schönbuchner I, Gevensleben H, Stoppa-Lyonnet D, Belotti M, Barjhoux L, Isaacs C, Peshkin BN, Caldes T, de la Hoya M, Cañadas C, Heikkinen T, Heikkilä P, Aittomäki K, Blanco I, Lazaro C, Brunet J, Agnarsson BA, Arason A, Barkardottir RB, Dumont M, Simard J, Montagna M, Agata S, D'Andrea E, Yan M, Fox S, Rebbeck TR, Rubinstein W, Tung N, Garber JE, Wang X, Fredericksen Z, Pankratz VS, Lindor NM, Szabo C, Offit K, Sakr R, Gaudet MM, Singer CF, Tea MK, Rappaport C, Mai PL, Greene MH, Sokolenko A, Imyanitov E, Toland AE, Senter L, Sweet K, Thomassen M, Gerdes AM, Kruse T, Caligo M, Aretini P, Rantala J, von Wachenfeld A, Henriksson K, Steele L, Neuhausen SL, Nussbaum R, Beattie M, Odunsi K, Sucheston L, Gayther SA, Nathanson K, Gross J, Walsh C, Karlan B, Chenevix-Trench G, Easton DF, Antoniou AC, et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21:134-47. [PMC free article: PMC3272407] [PubMed: 22144499]
  • Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E, Evans DG, Izatt L, Eeles RA, Adlard J, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Tischkowitz M, Douglas F, Hodgson S, Walker L, Porteous ME, Morrison PJ, Side LE, Kennedy MJ, Houghton C, Donaldson A, Rogers MT, Dorkins H, Miedzybrodzka Z, Gregory H, Eason J, Barwell J, McCann E, Murray A, Antoniou AC, Easton DF, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst. 2013;105:812-22. [PubMed: 23628597]
  • McLaughlin JR, Rosen B, Moody J, Pal T, Fan I, Shaw PA, Risch HA, Sellers TA, Sun P, Narod SA. Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst. 2013;105:141-8. [PMC free article: PMC3611851] [PubMed: 23257159]
  • Meeks HD, Song H, Michailidou K, Bolla MK, Dennis J, Wang Q, Barrowdale D, Frost D, McGuffog L, Ellis S, Feng B, Buys SS, Hopper JL, Southey MC, Tesoriero A, James PA, Bruinsma F, Campbell IG, Broeks A, Schmidt MK, Hogervorst FB, Beckman MW, Fasching PA, Fletcher O, Johnson N, Sawyer EJ, Riboli E, Banerjee S, Menon U, Tomlinson I, Burwinkel B, Hamann U, Marme F, Rudolph A, Janavicius R, Tihomirova L, Tung N, Garber J, Cramer D, Terry KL, Poole EM, Tworoger SS, Dorfling CM, van Rensburg EJ, Godwin AK, Guénel P, Truong T, Stoppa-Lyonnet D, Damiola F, Mazoyer S, Sinilnikova OM, Isaacs C, Maugard C, Bojesen SE, Flyger H, Gerdes AM, Hansen TV, Jensen A, Kjaer SK, Hogdall C, Hogdall E, Pedersen IS, Thomassen M, Benitez J, González-Neira A, Osorio A, Hoya Mde L, Segura PP, Diez O, Lazaro C, Brunet J, Anton-Culver H, Eunjung L, John EM, Neuhausen SL, Ding YC, Castillo D, Weitzel JN, Ganz PA, Nussbaum RL, Chan SB, Karlan BY, Lester J, Wu A, Gayther S, Ramus SJ, Sieh W, Whittermore AS, Monteiro AN, Phelan CM, Terry MB, Piedmonte M, Offit K, Robson M, Levine D, Moysich KB, Cannioto R, Olson SH, Daly MB, Nathanson KL, Domchek SM, Lu KH, Liang D, Hildebrant MA, Ness R, Modugno F, Pearce L, Goodman MT, Thompson PJ, Brenner H, Butterbach K, Meindl A, Hahnen E, Wappenschmidt B, Brauch H, Brüning T, Blomqvist C, Khan S, Nevanlinna H, Pelttari LM, Aittomäki K, Butzow R, Bogdanova NV, Dörk T, Lindblom A, Margolin S, Rantala J, Kosma VM, Mannermaa A, Lambrechts D, Neven P, Claes KB, Maerken TV, Chang-Claude J, Flesch-Janys D, Heitz F, Varon-Mateeva R, Peterlongo P, Radice P, Viel A, Barile M, Peissel B, Manoukian S, Montagna M, Oliani C, Peixoto A, Teixeira MR, Collavoli A, Hallberg E, Olson JE, Goode EL, Hart SN, Shimelis H, Cunningham JM, Giles GG, Milne RL, Healey S, Tucker K, Haiman CA, Henderson BE, Goldberg MS, Tischkowitz M, Simard J, Soucy P, Eccles DM, Le N, Borresen-Dale AL, Kristensen V, Salvesen HB, Bjorge L, Bandera EV, Risch H, Zheng W, Beeghly-Fadiel A, Cai H, Pylkäs K, Tollenaar RA, Ouweland AM, Andrulis IL, Knight JA, Narod S, Devilee P, Winqvist R, Figueroa J, Greene MH, Mai PL, Loud JT, García-Closas M, Schoemaker MJ, Czene K, Darabi H, McNeish I, Siddiquil N, Glasspool R, Kwong A, Park SK, Teo SH, Yoon SY, Matsuo K, Hosono S, Woo YL, Gao YT, Foretova L, Singer CF, Rappaport-Feurhauser C, Friedman E, Laitman Y, Rennert G, Imyanitov EN, Hulick PJ, Olopade OI, Senter L, Olah E, Doherty JA, Schildkraut J, Koppert LB, Kiemeney LA, Massuger LF, Cook LS, Pejovic T, Li J, Borg A, Öfverholm A, Rossing MA, Wentzensen N, Henriksson K, Cox A, Cross SS, Pasini BJ, Shah M, Kabisch M, Torres D, Jakubowska A, Lubinski J, Gronwald J, Agnarsson BA, Kupryjanczyk J, Moes-Sosnowska J, Fostira F, Konstantopoulou I, Slager S, Jones M, Antoniou AC, Berchuck A, Swerdlow A, Chenevix-Trench G, Dunning AM, Pharoah PD, Hall P, Easton DF, Couch FJ, Spurdle AB, Goldgar DE, et al. BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers. J Natl Cancer Inst. 2015;108: djv315. [PMC free article: PMC4907358] [PubMed: 26586665]
  • Mefford HC, Baumbach L, Panguluri RC, Whitfield-Broome C, Szabo C, Smith S, King MC, Dunston G, Stoppa-Lyonnet D, Arena F. Evidence for a BRCA1 founder mutation in families of West African ancestry. Am J Hum Genet. 1999;65:575-8. [PMC free article: PMC1377959] [PubMed: 10417303]
  • Mersch J, Jackson MA, Park M, Nebgen D, Peterson SK, Singletary C, Arun BK, Litton JK. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121:269-75. [PMC free article: PMC4293332] [PubMed: 25224030]
  • Metcalfe K, Gershman S, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, McLennan J, Eisen A, Foulkes WD, Rosen B, Sun P, Narod SA. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer. 2011a;104:1384-92. [PMC free article: PMC3101934] [PubMed: 21487411]
  • Metcalfe K, Lynch HT, Ghadirian P, Tung N, Kim-Sing C, Olopade OI, Domchek S, Eisen A, Foulkes WD, Rosen B, Vesprini D, Sun P, Narod SA. Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat. 2011b;127:287-96 [PubMed: 21221768]
  • Moghadasi S, Meeks HD, Vreeswijk MP, Janssen LA, Borg Å, Ehrencrona H, Paulsson-Karlsson Y, Wappenschmidt B, Engel C, Gehrig A, Arnold N, Hansen TVO, Thomassen M, Jensen UB, Kruse TA, Ejlertsen B, Gerdes AM, Pedersen IS, Caputo SM, Couch F, Hallberg EJ, van den Ouweland AM, Collée MJ, Teugels E, Adank MA, van der Luijt RB, Mensenkamp AR, Oosterwijk JC, Blok MJ, Janin N, Claes KB, Tucker K, Viassolo V, Toland AE, Eccles DE, Devilee P, Van Asperen CJ, Spurdle AB, Goldgar DE, García EG. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018;55:15-20. [PubMed: 28490613]
  • Molina-Montes E, Pérez-Nevot B, Pollán M, Sánchez-Cantalejo E, Espín J, Sánchez MJ. Cumulative risk of second primary contralateral breast cancer in BRCA1/BRCA2 mutation carriers with a first breast cancer: a systematic review and meta-analysis. Breast. 2014;23:721-42. [PubMed: 25467311]
  • Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-505. [PubMed: 30345884]
  • Moran A, O'Hara C, Khan S, Shack L, Woodward E, Maher ER, Lalloo F, Evans DG. Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations. Fam Cancer. 2012;11:235-42. [PubMed: 22187320]
  • Nyberg T, Frost D, Barrowdale D, Evans DG, Bancroft E, Adlard J, Ahmed M, Barwell J, Brady AF, Brewer C, Cook J, Davidson R, Donaldson A, Eason J, Gregory H, Henderson A, Izatt L, Kennedy MJ, Miller C, Morrison PJ, Murray A, Ong KR, Porteous M, Pottinger C, Rogers MT, Side L, Snape K, Walker L, Tischkowitz M, Eeles R, Easton DF, Antoniou AC. Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study. Eur Urol. 2020;77:24-35. [PMC free article: PMC6926480] [PubMed: 31495749]
  • Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62:145-58. [PMC free article: PMC1376797] [PubMed: 9443863]
  • Phelan CM, Kwan E, Jack E, Li S, Morgan C, Aubé J, Hanna D, Narod SA. A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families. Hum Mutat. 2002;20:352-7. [PubMed: 12402332]
  • Phillips KA, Milne RL, Rookus MA, Daly MB, Antoniou AC, Peock S, Frost D, Easton DF, Ellis S, Friedlander ML, Buys SS, Andrieu N, Noguès C, Stoppa-Lyonnet D, Bonadona V, Pujol P, McLachlan SA, John EM, Hooning MJ, Seynaeve C, Tollenaar RA, Goldgar DE, Terry MB, Caldes T, Weideman PC, Andrulis IL, Singer CF, Birch K, Simard J, Southey MC, Olsson HL, Jakubowska A, Olah E, Gerdes AM, Foretova L, Hopper JL. Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2013;31: 3091-9. [PMC free article: PMC3753701] [PubMed: 23918944]
  • Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, Solin LJ, Harris EE, Gaffney DK, Haffty BG, Dawson LA, Narod SA, Olivotto IA, Eisen A, Whelan TJ, Olopade OI, Isaacs C, Merajver SD, Wong JS, Garber JE, Weber BL. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1/2-associated stage I/II breast cancer. J Clin Oncol. 2006;24:2437-43. [PubMed: 16636335]
  • Rafnar T, Benediktsdottir KR, Eldon BJ, Gestsson T, Saemundsson H, Olafsson K, Salvarsdottir A, Steingrimsson E, Thorlacius S. BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Eur J Cancer. 2004;40:2788-93. [PubMed: 15571962]
  • Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26:2568-81. [PubMed: 18487574]
  • Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, Fraser L, Gentry-Maharaj A, Hayward J, Philpott S, Anderson C, Edlund CK, Conti D, Harrington P, Barrowdale D, Bowtell DD, Alsop K, Mitchell G, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Sieh W, McGuire V, Lester J, Bogdanova N, Dürst M, Hillemanns P, Odunsi K, Whittemore AS, Karlan BY, Dörk T, Goode EL, Menon U, Jacobs IJ, Antoniou AC, Pharoah PD, Gayther SA, et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107:djv214. [PMC free article: PMC4643629] [PubMed: 26315354]
  • Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C, Olopade OI, Neuhausen SL, van 't Veer L, Eeles R, Evans DG, Tomlinson G, Matloff E, Narod SA, Eisen A, Domchek S, Armstrong K, Weber BL, et al. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804-10 [PubMed: 16219936]
  • Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, Mazoyer S, Chenevix-Trench G, Easton DF, Antoniou AC, Nathanson KL, Laitman Y, Kushnir A, Paluch-Shimon S, Berger R, Zidan J, Friedman E, Ehrencrona H, Stenmark-Askmalm M, Einbeigi Z, Loman N, Harbst K, Rantala J, Melin B, Huo D, Olopade OI, Seldon J, Ganz PA, Nussbaum RL, Chan SB, Odunsi K, Gayther SA, Domchek SM, Arun BK, Lu KH, Mitchell G, Karlan BY, Walsh C, Lester J, Godwin AK, Pathak H, Ross E, Daly MB, Whittemore AS, John EM, Miron A, Terry MB, Chung WK, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Steele L, Neuhausen SL, Ding YC, Ejlertsen B, Gerdes AM, Hansen TV, Ramón y Cajal T, Osorio A, Benitez J, Godino J, Tejada MI, Duran M, Weitzel JN, Bobolis KA, Sand SR, Fontaine A, Savarese A, Pasini B, Peissel B, Bonanni B, Zaffaroni D, Vignolo-Lutati F, Scuvera G, Giannini G, Bernard L, Genuardi M, Radice P, Dolcetti R, Manoukian S, Pensotti V, Gismondi V, Yannoukakos D, Fostira F, Garber J, Torres D, Rashid MU, Hamann U, Peock S, Frost D, Platte R, Evans DG, Eeles R, Davidson R, Eccles D, Cole T, Cook J, Brewer C, Hodgson S, Morrison PJ, Walker L, Porteous ME, Kennedy MJ, Izatt L, Adlard J, Donaldson A, Ellis S, Sharma P, Schmutzler RK, Wappenschmidt B, Becker A, Rhiem K, Hahnen E, Engel C, Meindl A, Engert S, Ditsch N, Arnold N, Plendl HJ, Mundhenke C, Niederacher D, Fleisch M, Sutter C, Bartram CR, Dikow N, Wang-Gohrke S, Gadzicki D, Steinemann D, Kast K, Beer M, Varon-Mateeva R, Gehrig A, Weber BH, Stoppa-Lyonnet D, Sinilnikova OM, Mazoyer S, Houdayer C, Belotti M, Gauthier-Villars M, Damiola F, Boutry-Kryza N, Lasset C, Sobol H, Peyrat JP, Muller D, Fricker JP, Collonge-Rame MA, Mortemousque I, Nogues C, Rouleau E, Isaacs C, De Paepe A, Poppe B, Claes K, De Leeneer K, Piedmonte M, Rodriguez G, Wakely K, Boggess J, Blank SV, Basil J, Azodi M, Phillips KA, Caldes T, de la Hoya M, Romero A, Nevanlinna H, Aittomäki K, van der Hout AH, Hogervorst FB, Verhoef S, Collée JM, Seynaeve C, Oosterwijk JC, Gille JJ, Wijnen JT, Gómez Garcia EB, Kets CM, Ausems MG, Aalfs CM, Devilee P, Mensenkamp AR, Kwong A, Olah E, Papp J, Diez O, Lazaro C, Darder E, Blanco I, Salinas M, Jakubowska A, Lubinski J, Gronwald J, Jaworska-Bieniek K, Durda K, Sukiennicki G, Huzarski T, Byrski T, Cybulski C, Toloczko-Grabarek A, Złowocka-Perłowska E, Menkiszak J, Arason A, Barkardottir RB, Simard J, Laframboise R, Montagna M, Agata S, Alducci E, Peixoto A, Teixeira MR, Spurdle AB, Lee MH, Park SK, Kim SW, Friebel TM, Couch FJ, Lindor NM, Pankratz VS, Guidugli L, Wang X, Tischkowitz M, Foretova L, Vijai J, Offit K, Robson M, Rau-Murthy R, Kauff N, Fink-Retter A, Singer CF, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Berger A, Greene MH, Mai PL, Imyanitov EN, Toland AE, Senter L, Bojesen A, Pedersen IS, Skytte AB, Sunde L, Thomassen M, Moeller ST, Kruse TA, Jensen UB, Caligo MA, Aretini P, Teo SH, Selkirk CG, Hulick PJ, Andrulis I, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313:1347-61. [PMC free article: PMC4537700] [PubMed: 25849179]
  • Reiner AS, Robson ME, Mellemkjær L, Tischkowitz M, John EM, Lynch CF, Brooks JD, Boice JD, Knight JA, Teraoka SN, Liang X, Woods M, Shen R, Shore RE, Stram DO, Thomas DC, Malone KE, Bernstein L, Riaz N, Woodward W, Powell S, Goldgar D, Concannon P, Bernstein JL, et al. Radiation treatment, ATM, BRCA1/2, and CHEK2*1100delC pathogenic variants and risk of contralateral breast cancer. J Natl Cancer Inst. 2020;112:1275-9. [PMC free article: PMC7735763] [PubMed: 32119081]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA.Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006;98:1694-706. [PubMed: 17148771]
  • Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung N, Armstrong A, Wu W, Goessl C, Runswick S, Conte P. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-33. [PubMed: 28578601]
  • Robson M, Svahn T, McCormick B, Borgen P, Hudis CA, Norton L, Offit K. Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series. Cancer. 2005;103:44-51. [PubMed: 15558796]
  • Robson ME, Chappuis PO, Satagopan J, Wong N, Boyd J, Goffin JR, Hudis C, Roberge D, Norton L, Bégin LR, Offit K, Foulkes WD. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res. 2004;6:R8-R17. [PMC free article: PMC314444] [PubMed: 14680495]
  • Rosen EM, Fan S, Ma X. BRCA1 regulation of transcription. Cancer Lett. 2006;236:175-85 [PubMed: 15975711]
  • Sankaran S, Starita LM, Simons AM, Parvin JD. Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function. Cancer Res. 2006;66:4100-7 [PubMed: 16618730]
  • Satagopan JM, Boyd J, Kauff ND, Robson M, Scheuer L, Narod S, Offit K. Ovarian cancer risk in Ashkenazi Jewish carrier of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8:3776-81. [PubMed: 12473589]
  • Seynaeve C, Verhoog LC, van de Bosch LM, van Geel AN, Menke-Pluymers M, Meijers-Heijboer EJ, van den Ouweland AM, Wagner A, Creutzberg CL, Niermeijer MF, Klijn JG, Brekelmans CT. Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy. Eur J Cancer. 2004;40:1150-8. [PubMed: 15110878]
  • Spurdle AB, Whiley PJ, Thompson B, Feng B, Healey S, Brown MA, Pettigrew C, Van Asperen CJ, Ausems MG, Kattentidt-Mouravieva AA, van den Ouweland AM, Lindblom A, Pigg MH, Schmutzler RK, Engel C, Meindl A, Caputo S, Sinilnikova OM, Lidereau R, Couch FJ, Guidugli L, Hansen TV, Thomassen M, Eccles DM, Tucker K, Benitez J, Domchek SM, Toland AE, Van Rensburg EJ, Wappenschmidt B, Borg Å, Vreeswijk MP, Goldgar DE, et al. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet. 2012;49:525-32. [PMC free article: PMC3810416] [PubMed: 22889855]
  • Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401-8. [PubMed: 9145676]
  • Swanson CL, Bakkum-Gamez JN. Options in prophylactic surgery to prevent ovarian cancer in high-risk women. How new hypotheses of fallopian tube origin influence recommendations. Curr Treat Options Oncol. 2016;17:20. [PubMed: 27032642]
  • Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:1811-4. [PMC free article: PMC2267289] [PubMed: 18042939]
  • Thompson D, Easton DF. The breast cancer linkage consortium. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358-65. [PubMed: 12237281]
  • Truty R, Paul J, Kennemer M, Lincoln SE, Olivares E, Nussbaum RL, Aradhya S. Prevalence and properties of intragenic copy-number variation in Mendelian disease genes. Genet Med. 2019;21:114-23. [PMC free article: PMC6752305] [PubMed: 29895855]
  • Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmaña J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr, et al. Adjuvant olaparib for patients with BRCA1-or BRCA2-mutated breast cancer. N Engl J Med. 2021;384:2394-405. [PMC free article: PMC9126186] [PubMed: 34081848]
  • Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23:1111-30 [PubMed: 15057881]
  • van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF, Ausems MG, Menko FH, Gomez Garcia EB, Klijn JG, Hogervorst FB, van Houwelingen JC, van't Veer LJ, Rookus MA, van Leeuwen FE, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet . 2005;42:711-9. [PMC free article: PMC1736136] [PubMed: 16141007]
  • van den Broek AJ, Schmidt MK, van 't Veer LJ, Tollenaar RA, van Leeuwen FE. Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what's the evidence? A systematic review with meta-analysis. PLoS One. 2015;10:e0120189. [PMC free article: PMC4376645] [PubMed: 25816289]
  • van den Broek AJ, van 't Veer LJ, Hooning MJ, Cornelissen S, Broeks A, Rutgers EJ, Smit VT, Cornelisse CJ, van Beek M, Janssen-Heijnen ML, Seynaeve C, Westenend PJ, Jobsen JJ, Siesling S, Tollenaar RA, van Leeuwen FE, Schmidt MK. Impact of age at primary breast cancer on contralateral breast cancer risk in BRCA1/2 mutation carriers. J Clin Oncol. 2016;34:409-18. [PubMed: 26700119]
  • van der Kolk DM, de Bock GH, Leegte BK, Schaapveld M, Mourits JE, de Vries J, van der Hout AH, Oosterwijk JC. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. Breast Cancer Res Treat. 2010;124:643-51. [PubMed: 20204502]
  • Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171-82 [PubMed: 11832208]
  • Verhoog LC, Berns EM, Brekelmans CT, Seynaeve C, Meijers-Heijboer EJ, Klijn JG. Prognostic significance of germline BRCA2 mutations in hereditary breast cancer patients. J Clin Oncol. 2000;18:119S-24S. [PubMed: 11060339]
  • Vichapat V, Garmo H, Holmqusit M, Liljegren G, Warnberg F, Llambe M, Fornander T, Adolfsson J, Luchtenborg M, Holmberg L. Tumor stage affects risk and prognosis of contralateral breast cancer: results from a large Swedish-population-based study. J Clin Oncol. 2012;30:3478-85. [PubMed: 22927521]
  • Weischer M, Bojesen SE, Tybjaerg-Hansen A, Axelsson CK, Nordestgaard BG. Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol. 2007;25:57-63. [PubMed: 16880452]
  • Whittemore AS, Gong G, John EM, McGuire V, Li FP, Ostrow KL, Dicioccio R, Felberg A, West DW. Prevalence of BRCA1 mutation carriers among U.S. non-Hispanic whites. Cancer Epidemiol Biomarkers Prev. 2004;13:2078-83. [PubMed: 15598764]
  • Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, Dunning AM, Redman J, Scarth J, Plaskocinska I, Luccarini C, Shah M, Pooley K, Dorling L, Lee A, Adank MA, Adlard J, Aittomäki K, Andrulis IL, Ang P, Barwell J, Bernstein JL, Bobolis K, Borg Å, Blomqvist C, Claes KBM, Concannon P, Cuggia A, Culver JO, Damiola F, de Pauw A, Diez O, Dolinsky JS, Domchek SM, Engel C, Evans DG, Fostira F, Garber J, Golmard L, Goode EL, Gruber SB, Hahnen E, Hake C, Heikkinen T, Hurley JE, Janavicius R, Kleibl Z, Kleiblova P, Konstantopoulou I, Kvist A, Laduca H, Lee ASG, Lesueur F, Maher ER, Mannermaa A, Manoukian S, McFarland R, McKinnon W, Meindl A, Metcalfe K, Mohd Taib NA, Moilanen J, Nathanson KL, Neuhausen S, Ng PS, Nguyen-Dumont T, Nielsen SM, Obermair F, Offit K, Olopade OI, Ottini L, Penkert J, Pylkäs K, Radice P, Ramus SJ, Rudaitis V, Side L, Silva-Smith R, Silvestri V, Skytte AB, Slavin T, Soukupova J, Tondini C, Trainer AH, Unzeitig G, Usha L, van Overeem Hansen T, Whitworth J, Wood M, Yip CH, Yoon SY, Yussuf A, Zogopoulos G, Goldgar D, Hopper JL, Chenevix-Trench G, Pharoah P, George SHL, Balmaña J, Houdayer C, James P, El-Haffaf Z, Ehrencrona H, Janatova M, Peterlongo P, Nevanlinna H, Schmutzler R, Teo SH, Robson M, Pal T, Couch F, Weitzel JN, Elliott A, Southey M, Winqvist R, Easton DF, Foulkes WD, Antoniou AC, Tischkowitz M. Cancer Risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38:674-85. [PMC free article: PMC7049229] [PubMed: 31841383]
  • Yates MS, Meyer LA, Deavers MT, Daniels MS, Keeler ER, Mok SC, Gershenson DM, Lu KH. Microscopic and early-stage ovarian cancers in BRCA1/2 mutation carriers: building a model for early BRCA-associated tumorigenesis. Cancer Prev Res (Phila). 2011;4:463-70. [PMC free article: PMC3048908] [PubMed: 21278312]
  • Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT. Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res. 2015;21:211-20. [PMC free article: PMC4286460] [PubMed: 25348513]
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