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Nelson HD, Huffman LH, Fu R, et al. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Sep. (Evidence Syntheses, No. 37.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility [Internet].

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Appendix I. Evidence Table of Studies of Prevalence and Penetrance

Author, yearData typeData source /Parent studySettingPopulationInclusion / Exclusion criteriaCountryRace or ethnicityStudy designPrimary risk measureFamily history / Risk level definitionNParticipation rateGenes includedLaboratory methodsTissue sourceParts of genes studiedDemographicsConclusionsStudy qualityDefinition of clinically significant
Abeliovich et al, 1997152 Prev-CAHigh-risk breast cancer or genetics clinicBreast cancer: prevalent Inclusion: Jewish women with breast and/or ovarian cancer referred from outpatient oncology clinic or oncogenetic counseling clinicIsraelAshkenazi Jewish (199) and non-Ashkenazi Jewish (44)Case seriesPrevalenceDefinite positive family history: 3 or more 1st degree relatives with breast and/or ovarian cancer.243Not reported BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/A82% Ashkenazi JewishMutation prevalence for Ashkenazi Jewish women with ovarian cancer is 62%, with breast cancer diagnosed <40 is 30%, with breast cancer diagnosed >40 is 10%.Cancer is verified, presumably.Ashkenazi Jewish founder mutations
The founder mutations 185delAG and 5382insC in BRCA1and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women Ovarian cancer: prevalent if incidentAt least one 1st-, 2nd-, or 3rd-degree female relative with breast or ovarian cancer.18% non-Ashkenazi JewishAshkenazi Jewish founder mutation only
Clinic—“most” agreed, referrals from one genetic clinic
Prevalent cases—possible bias
Anglian Breast Cancer Study Group, 200027 Pen & Prev-CAAnglian Breast Cancer Study GroupCancer registryBreast cancer: prevalent Inclusion:
1.

Women

2.

diagnosed < 55 years of age

3.

diagnosed 1/1/1991 – 6/30/1996, alive 7/1/1996

UK, East AngliaUnselectedCase series: prevalencePrevalence Actual risk: method for calculating risk: home-grown methods applied to family dataN/AIndividuals: 1,435Group description: breast cancer cases BRCA1 and BRCA2 Screening with confirmation by sequencing: MHABloodEntire coding regionAge: not specifiedMutations in BRCA1/BRCA2 are rare in the population and account for a small proportion of breast cancer. Account for less than 1/5 of familial breast cancer risk.Cancer verified: yes, probands; proband report, relativesPredicted to encode a truncated protein
Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases other: Pedigrees of breast cancer probandsFamilies: penetranceRelative risk: comparison group for relative risk: population ratesFamilies: 23Participation rate: 71% contacted, 51% total groupIntron-exon boundariesGender: 100% womenCompleteness of mutation identification: estimated 63% sensitivity
2,805 eligibleRace/ethnicity: not specifiedEvidence of bias: relatives of younger-onset cases
569 died
200 MD refused
2,028 contacted
1,435 blood sample
85% amplified OK > 1,220 effective sample size
Anton-Culver et al, 2000144 Prev-CACancer registry (probands)Breast cancer: incident Inclusion:
1.

men & women, USA, unselected

2.

all breast cancer cases aged 18+ diagnosed in Orange County, CA, from 3/1/94 to 3/1/95 and all ovarian cancer cases diagnosed 3/1/94 to 3/1/95.

3.

Probands from Cancer Surveillance Program of Orange County (CSPOC) cancer registry.

USAUnselectedCase seriesPrevalenceFamily history: 1 or more 1st degree relative with breast or ovarian cancer or 2 or more 2nd degree relatives with breast or ovarian cancer on the same side of the family.2,030 probands: 342 ovarian cancer, 17 male breast cancer, 1,671 female breast cancer cases. 362 breast and 70 ovarian cancer patients refused to participate.Ovarian cancer: 272/342 (79.5%) BRCA1 Selected mutations: breast cancer, 7 mutationsBloodN/A673 female breast cancer probands, 120 ovarian cancer probands. 29% of breast and 38% of ovarian cancer probands under age 50 at diagnosis. 9 breast cancer probands were male. 4.5% of breast and 3.3% of ovarian cancer probands were Ashkenazi Jewish. BRCA1 mutation prevalence: 1.6% (0.8–2.9) for females with breast cancer and 3.3% (0.8–8.3) for ovarian cancer cases. No mutations were found among non-white cases. Positive family history of breast or ovarian cancer is significantly associated with BRCA1 mutation status among breast and ovarian cancer probands.Cancer was verified through pathology report, clinical record, death certificate, interview with 2nd relative; pathology review breast/ovarian cancer 100% probands, 76% 1st-degree, 65% 2nd-degreeAshkenazi Jewish founder mutations; BRCA1 - R841W, int5-IIT-G, 2594delC, 3600del-AAGATACTAGT, 962delCTCA
Characteristics of BRCA1 mutations in a population-based case series of breast and ovarian cancer Ovarian cancer: incidentFemale breast cancer: 1,310/1,671 (82%)Screening only: breast cancer for above mutations, Allele-specific oligonucleotideMean age for breast cancer cases: 58.4
Male breast cancer: 16/17 (94.1%)(ASO); ovarian cancer: RNase mismatch cleavage assayMean age for ovarian cancer cases: 55.3
Antoniou et al, 200228 Pen & Prev-CAAnglian Breast Cancer (ABC)Cancer registry (ABC Study)Breast cancer: prevalent (ABC Study)See Anglian Breast Cancer Study Group, 2002UKUnselectedCase series (ABC)PrevalenceNot reported1,484 cases and 156 familiesNot reported BRCA1 and BRCA2 Screening with confirmation by sequencing: CSGEBloodEntire coding regionNot reportedABC: 8 (0.5%) BRCA1 and 15 (1.0%) BRCA2 mutationsWas not clear if B group's cancer was verified.Thought to be disease-causing, not otherwise specified
A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes Study Multiple case families (B families)Referred families (B)Other: pedigrees of breast cancer probands Inclusion: 2 or more breast cancer cases (1 diagnosed <50)Convenience sample (B)Intron-exon boundaries (see Anglian Breast Cancer Study Group, 2000)B: 21 (13.5%) BRCA1 and 18 (11.5%) BRCA2 mutations among index casesScreening with sequencing.
Family history of breast and/or ovarian cancer (B)B: referral, volunteer.
Evidence of bias with prevalent cases.
Antoniou et al, 2003130 PenOther: meta-analysisBreast cancer: prevalent and incident Inclusion:
1.

women

2.

men

3.

age at diagnosis: varied by study

4.

enumeration of all 1st degree relatives of identified mutation carriers

USA, Australia, Canada, Israel, Finland, Hungary, Hong Kong, Iceland, Italy, Poland, Sweden, UKSelection varies by studyFamiliesActual risk: method for calculating risk: segregation analysis of family dataN/A280 families of BRCA1+Varied by study BRCA1 and BRCA2 Varied by studyBloodVaried by studyAge: not specified (some studies included only the families of early-onset breast cancer cases)Pattern of risks similar to those in multiple-case families, but absolute magnitudes were lower, especially for BRCA2. Risks in carriers were higher among relatives of breast cancer cases diagnosed at < 35 years.Estimated risks higher because estimates are from relatives of individuals diagnosed with breast cancer.“Pathogenic” according to generally accepted criteria (BIC website): frame shift or nonsense mutations, splice site mutations predicted to cause aberrant splicing, large deletions or duplications, and miss sense mutations classified as such by BIC (included only mutations in the ring-finger domain of BRCA1)
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 Ovarian cancer: prevalent and incident218 families of BRCA2+Approximate range: 25–80%From ethnic-specific testing to sequencingGender: not specified (3 studies included male breast cancer cases); risks are calculated for womenCancer diagnoses in relatives confirmed in some studies, but not others.
Race/ethnicity: varied by studyTechniques for mutation detection varied widely.
Analyses assume Mendelian segregation of the mutation.
Boyd et al, 2000154 Prev-CAComprehensive cancer centerOvarian cancer: incident Inclusion:
1.

ovarian cancer diagnosed

2.

treated at specific cancer center

3.

diagnosed between December 1986 and August 1998

4.

Jewish origin

5.

women

USAJewish originCase seriesPrevalenceN/A189N/A BRCA1and BRCA2 Selected mutations: Ashkenazi Jewish panel All mutations confirmed as germline through analysis of DNA from non-tumor tissueTissue specimenN/A100% women of Jewish origin.Age at ovarian cancer diagnosis is younger in BRCA1 and BRCA2 mutation carriers. Age at diagnosis for BRCA2 mutation carriers is similar to non-carriers. Mutation frequency:Cancer was verified.Ashkenazi Jewish founder mutations
Clinicopathologic features of BRCA-linked and sporadic ovarian cancer Mean age at diagnosis for BRCA1 cases = 54 years (SD 11) (n=67). BRCA1: 35%Ashkenazi Jewish panel only.
Mean age at diagnosis for BRCA2 cases = 62 years (SD 10) (n=21). BRCA2: 11%Tissue was available for all subjects. National Cancer Institute (NCI) comprehensive cancer center may have more advanced and complicated cases.
Mean age at diagnosis for sporadic, nonhereditary cases = 63 years (SD 12) (n=101)Survival in noncarriers is comparable to that for participants in clinical trials.
Brose et al, 200221 PenUniversity of Michigan, University of PennsylvaniaHigh-risk breast cancer clinic or genetics clinicFamilies seeking breast cancer risk counseling with documented deleterious BRCAmutations in family Inclusion: Documented deleterious BRCA1 mutation in familyUSAUnselectedFamiliesActual risk: method for calculating risk: home-grown method applied to family dataN/A147 familiesNot relevant BRCA1 Clinical testingBloodNot statedGender and ages:Cancer risk estimates higher than in population-based studies, and lower than in linkage studies. May better represent risks for those identified in risk evaluation clinics.Cancer verified: not statedAshkenazi Jewish founder mutations; others judged to be clinically significant as part of clinical testing
Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program Breast cancer risk assessment clinicsRelative risk: comparison group: population ratesIncludes presumed carriersWomen ≤ 30 3%, 31–40 15%, 41–50 28%, 51–60 24%, 61–70 15%, >70 14%.Completeness of mutation identification: presumably excellent—clinical testing
Men < 30 3%, 31–40 10%, 41–50 17%, 51–60 20%, 61–70 17%, >70 34%.Participation rate: N/A
Race/Ethnicity: Caucasian 95%, African American, Asian, Native American 5%Evidence of bias: intentional referral population, no consideration of prophylactic surgeries, missing data—excluded individuals
Couch et al, 199736 Prev-CAHigh-risk breast cancer clinicBreast cancer: prevalent Inclusion: Women with breast cancer. Familial risk factor for breast cancer or diagnosis before age 40USAUnselectedCase seriesPrevalenceFamily history: 1 to 11 cases of breast cancer per family263No patient refused to participate in the study BRCA1 Screening with confirmation by sequencing: CSGE exons 2,3 & 5–24BloodEntire coding region Intron-exon boundariesFor 169 women with familial risk factors: Mean age at diagnosis in families: BRCA1 mutation frequency: 16% family history of breast cancerCancer is presumably verified.Ashkenazi Jewish founder mutations; other mutations not specified
BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer <35 – 39%7% family history of breast cancer but no ovarian cancer95–99% sensitivity
35–39 – 16%13% breast cancer diagnosed <40 years oldRepresentative of patients seen in referral clinics for inherited breast cancer risk
40–44 – 19%Even in women from high-risk families, the majority of BRCA1 mutation test results will be negative and therefore uninformative
45–49 – 14%
50–54 – 20%
55–59 – 14%
≥ 60 – 14%
94 women diagnosed before 40 years of age
Eccles et al, 1998141 Prev-CAHigh-risk breast cancer clinic or genetics clinicBreast cancer Inclusion:
1.

women

2.

for Group 1: Diagnosed < 40 years

3.

for Group 2: Bilateral breast cancer diagnosed ≥ 40 years

4.

for Group 3: Strong family history of breast/ovarian cancer and DNA sample available from affected relative

EnglandUnselectedCase seriesPrevalenceAt least 2 relatives with breast cancer with average diagnosis age ≤ 40 years or at least 1 relative with breast cancer diagnosed < 45 years plus 1 relative with ovarian cancer diagnosed < 60 years.230Not reported BRCA1 Screening with confirmation by sequencing: heteroduplex (HD) and SSCP analysisBloodEntire coding regionNot reported18 protein-truncating mutations identifiedCancer was verified through family members, medical records, and death certificates when available.Protein-truncating mutation
BRCA1 mutations in southern England Family history or breast and/or ovarian cancerGroup 1: 155Group 1: 6.5%Only screening for mutation.
Group 2: 45Group 2: NoneCannot evaluate the participation rate.
Group 3: 30Group 3: 26.7%Likely prevalent cases have bias.
FitzGerald et al, 1996150 Prev-CABreast cancer referral centersBreast cancer: prevalent Inclusion: Women diagnosed with breast cancer at or before age 40 between 1981 and 1992USAUnselectedCase seriesPrevalenceNot reported418418 of 850 eligible women (49%) BRCA1 Selected mutations: 185delAG—Jewish womenBloodEntire coding region418 women, of whom 39 were Jewish (9.3%)Among 30 women with breast cancer diagnosed <30, 13% had definite, chain-termination mutations. Among 39 Jewish women with breast cancer diagnosed before ≤ 40, 21% had 185delAG mutation.Cancer was verified. BRCA1 only—good for diagnosis <30.Premature protein truncation, unambiguous inactivation of the gene product
Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer 30 diagnosedScreening diagnosed <30: protein transcription translation (PTT) analysisLow participation rate—no information provided on comparability of participants and non-participants.
<30Possible survivor bias.
39 Jewish
Fodor et al, 1998125 Prev-COHospital for breast cancer casesBreast cancer: incident Inclusion: USAAshkenazi JewishCase-controlPrevalence Actual risk: case-control data combined with population incidence ratesHigh-risk: at least three 1st- or 2nd-degree relatives with breast cancer268 breast cancer cases90% for breast cancer cases BRCA1 and BRCA2 Ashkenazi Jewish panelBlood and tissue blocks from casesN/A Prenatal Screening Group: Mean age 35 Carrier frequency: Cancer was verified. Only did Ashkenazi Jewish panel. 90% participation rate for cases. No bias found.Ashkenazi Jewish founder mutations
Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients Prev- CAGeneral populationAshkenazi Jewish men and women referred for prenatal carrier testing Controls: men and women undergoing prenatal screeningRelative risk: comparison group was part of the study and population rates1,715 prenatal screening group Breast Cancer Cases:Mean age at diagnosis 58.7 (range 35–90)Breast cancer cases 7%
Cases: Ashkenazi Jewish women who had surgery for breast cancerPrenatal screening group 2%
Lifetime risk of breast cancer for carriers 36%
Ford et al, 1998131 PenBCLCBCLCFamily history of breast and/or ovarian cancer Inclusion: Family contained at least 4 cases of either female breast cancer diagnosed <60 years or male breast cancer diagnosed at any ageUSA, UK, Canada, Europe, IcelandUnselectedFamiliesActual risk: segregation analysis of family dataAt least 4 cases of either female breast cancer diagnosed <60 years or male breast cancer diagnosed at any age237 familiesNot reported BRCA1 and BRCA2 Sequencing—subsetBloodN/ANot reportedCumulative breast cancer risk: by age 50, 28%; by age 70, 84%Not all families genotyped at BRCA1/BRCA2. Estimated sensitivity 63%. No information on participation rate. Multiple case families—suitable for linkage analysis.Linkage data: flanking markers for BRCA1 and BRCA2, LoD scores BRCA1 and BRCA2 mutations not stated
Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families Screening—various subsetCumulative ovarian cancer risk: by age 50, 0.4%; by age 70, 27%
Flanking markersPossibly a lower breast cancer risk in BRCA2 mutation carriers < 50 years old
Frank et al, 199894 Prev-CAHigh-risk breast cancer clinicBreast cancer: prevalent Inclusion:
1.

diagnosed with invasive breast cancer <50 years or ovarian cancer at any age

2.

at least one 1st- or 2nd-degree relative with either breast or ovarian cancer

USAUnselectedCase seriesPrevalenceAt least one 1st- or 2nd-degree relative with either breast or ovarian cancer238Not reported BRCA1 and BRCA2 SequencingBloodEntire coding region84% had diagnosis of breast cancer <50 years, with no ovarian cancer Mutation frequency: Overall: 39%Cancer was verified by probands. Good sequencing.Led to premature truncation of the BRCA1 protein product at least 10 amino acids from the C-terminus or premature truncation of the BRCA2 protein product at least 270 amino acids from the C-terminus
Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk Exclusion:
1.

relative with a known mutation in BRCA1 or BRCA2

2.

family had been determined by linkage to carry a mutation in one of these genes

49% reported a history of ovarian cancer in themselves or at least one relativeWith ovarian cancer in family: 50%No information participation rate. Prevalent cases bias.
Without ovarian cancer in family: 29%
Frank et al, 200233 Prev-COClinical patient careBreast cancer: prevalentClinical testingUSAUnselectedConsecutive series testedPrevalenceNot stated10,000Not relevant BRCA1 and BRCA2 SequencingBloodEntire coding regionAge: median 49 (range 6–97) Mutation frequency: Cancer was presumably verified for cases and family members. Sequencing good. Possible survivor bias.Prematurely terminals the protein product of BRCA1 at least 10 amino acids from the C-terminus or the protein product of BRCA2 at least 110 amino acids from the C-terminus.
Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals Ovarian cancer: prevalentGender: 90% womenWomen with breast cancer: 20%Specific miss sense mutations and non-coding intervening sequence mutations—based on data derived from linkage analysis of high-risk families, functional assays, biochemical evidence, or demonstration of abnormal mRNA transcript processing.
Family history of breast and/or ovarian cancerRace/ethnicity: 30% Ashkenazi JewishWomen with ovarian cancer: 34%A few mutations: reservable presumption that the mutation was deleterious and reported as suspected deleterious.
41% Northern/Western European
Gayther et al, 1999149 Prev-CAUKCCCR StudyNational study of familial ovarian cancerOvarian cancer Inclusion: Families containing 2 or more 1st- or 2nd-degree relatives with ovarian cancerEnglandUnselectedFamiliesPrevalenceTwo or more 1st- or 2nd-degree relatives diagnosed with epithelial ovarian cancer at any age112 familiesNot reported BRCA1 and BRCA2 Screening with confirmation by sequencing: Protein truncation test and SSCA/HABloodEntire coding regionNot reportedMutation prevalence: 43%Pathology report of death certificate verified for at least 2 ovarian cancer cases.Predicted to result in premature truncation of BRCA1 protein.
The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: no evidence for other ovarian cancer-susceptibility genes Screening only: specific duplication (BRCA1) BRCA1 prevalence: 36%Screening for coding regions good.Expected to affect splicing, predicted to abolish highly conserved splice-site consensus sequences.
BRCA2 prevalence: 7%Cannot evaluate participation rate or evidence of bias. BRCA1 Pro 1749Arg—functional studies suggest that it is functionally significant.
Extent of breast/ovarian cancer family history strongly predictive of BRCA1 mutation status BRCA2 pathogenic mutations: frame shift deletion, nonsense mutation.
Gershoni-Baruch et al, 2000151 Prev-CAClinicBreast cancer: prevalent Inclusion: Diagnosed with breast cancer≤ 42 yearsIsraelJewishCase-seriesPrevalence1st or 2nd degree relative with breast/ovarian cancer172Not reported BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/AMean age at cancer diagnosis: 37 (range 25–42) Mutation frequency: Overall: 31%Cancer was verified.Ashkenazi Jewish founder mutations
Significantly lower rates of BRCA1/BRCA2 founder mutations in Ashkenazi women with sporadic compared with familial early onset breast cancer 46% had family history of breast/ovarian cancerFamily history of breast and/or ovarian cancer: 57%Ashkenazi Jewish panel only.
95% Ashkenazi JewishNo such family history: 10%No information on participation rate. Possible survivor bias.
Hartge et al, 199986 Prev-COGeneral populationBreast and/or ovarian or other cancer: prevalent Inclusion: Adult men and womenUSAJewishConvenience samplePrevalenceAt least one 1st-degree relative with breast/ovarian cancer5,318Not relevant BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/AMedian age at diagnosis:Most important predictor of having a mutation is previous diagnosis of breast and/or ovarian cancer. For men and women without cancer, family history of breast cancer diagnosed <50 years was strongest predictor.Cancer was not verified.Ashkenazi Jewish founder mutations
The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews Prev- CAResponders to advertisement50 yrsAshkenazi Jewish panel only.
30% maleAd responders. Cancer cases—possible survivor bias.
8% women with breast cancerGeneral—volunteer; possibly more likely to have a positive family history.
3% men with prostate cancer
Hopper et al, 1999132 Pen & Prev-CAAustralian Breast Cancer Family Study, SydneyCancer registryBreast cancer: incident Inclusion: Women under 40 years at time of diagnosisAustraliaUnselectedFamiliesActual risk: home-grown method applied to family dataAt least one 2nd degree relative affected with cancer388 casesInterviewed 73% BRCA1 and BRCA2 Screening with confirmation by sequencing: MHA, protein truncation testBloodExon 2, 11 & 20 BRCA1 Not reportedFamily history of breast cancer was not a strong predictor of mutation status in this setting. Risk in mutation carriers was, on average, 9 times the population risk (95% CI 4–23). Penetrance to age 70 was 40% (95% CI 15–65%), about half that estimated from BCLC families.Cancer verified in cases—excellentProtein-truncating mutation
Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2 Segregation analysis of family dataBlood drawn in 90% with affected 1st degree relativeExon 10 & 11 BRCA2 Family members—very good (verification of reported cancer sought through records)
Relative risk: population ratesBlood drawn in 82% without affected 1st degree relativeMutation identification was fair (2/3 coding region).
Blood drawn on 60% of total groupParticipation rate was fair, no differences in measured risk factors.
Janezic et al, 1999148 Prev-CACancer registryOvarian cancer: incident Inclusion: Diagnosed between 3/94–2/95USAUnselectedCase seriesPrevalenceAt least one 1st-degree relative with breast cancer diagnosed before 50 years or ovarian cancer10782% BRCA1 Screening with confirmation by sequencing: RNase mismatch cleavage assayBloodEntire coding regionMean age at cancer diagnosed: 55.04 100% womenSeveral variants (novel and characterized) and a rare form of the Q356R polymorphism were associated with a family history of cancer, suggesting that these may influence ovarian cancer risk.Cancer was verified.Protein-truncating mutation
Germline BRCA1 alterations in a population-based series of ovarian cancer cases BRCA1 only—good identification, screening.
Good participation rate—82%; no analysis of possible bias.
King et al, 2003134 Pen & Prev-CACancer centerBreast cancer: incident Inclusion: Diagnosed between 9/96–12/00USAAshkenazi JewishRetrospective CohortActual risk: survival analysis for relatives who have a confirmed BRCA1/BRCA2 mutationAshkenazi Jewish1,008 probands 104 families Number of BRCA1/2 mutation positive family members not statedNot reported BRCA1 and BRCA2 Ashkenazi Jewish panelBlood Archived tissue—deceased family membersN/AAge at diagnosisLifetime risk of breast cancer among women mutation carriers is 82%, similar to risk in families with many cases.Cancer was verified through probands, presumably.Ashkenazi Jewish founder mutations
Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 10% <40Relatives confirmed by pathology report or death certificate. Ashkenazi Jewish panel only. No info on participation rate. No evidence of bias.
13% 40–44
19% 45–49
30% 50–59
27% 60+
Langston et al, 1996142 Prev-CADaling et al, 1994244 Cancer registryBreast cancer: prevalent Inclusion:
1.

early onset breast cancer diagnosed before age 35

2.

Caucasian

3.

not selected on basis of family history

4.

born after 1944

5.

diagnosed between 1/1/1983 and 4/30/1990

6.

residents of King, Pierce, or Snohomish County in Washington state

7.

women

8.

identified through the Cancer Surveillance System

USACaucasianPopulation-based, case-controlPrevalenceAt least one 1st-degree relative with breast/ovarian cancer. At least one 2nd-degree relative (no 1st-degree) with breast/ovarian cancer8084% interviewed BRCA1 Screening with confirmation by sequencing: SSCPs. Allele-specific oligonucleotidesBloodEntire coding region, intron-exon boundaries promoter region100% Caucasian women.Alterations in BRCA1 identified in ~10% of young women with breast cancer, and were not limited to those with a positive family history of breast/ovarian cancer.Cancer was verified.Associated with breast cancer in previous studies of high-risk families or predicted to result in protein truncation.
BRCA1 mutations in a population-based sample of young women with breast cancer 52% of those interviewed gave blood sample Age at diagnosis for all women with breast cancer before age 35 (n=214): Completeness of mutation was okay—screening. Low participation rate.
37% of overall were age eligible21–30 age range = 70 (33%)Participants: 94% alive; 19% in situ. Non-participants: 66% alive; 69% in situ. Survivors less extensive breast cancer
31–34 age range = 143 (67%)
Age at diagnosis for women tested for BRCA1 before age 35 (n=80):
21–30 age range = 26 (32%)
31–34 age range = 54 (68%)
Liede et al, 2002129 Pen & Prev-CAGilda Radner Ovarian Cancer Detection ProgramOvarian cancer screening program based in a major medical centerHealthy women with a family history of breast cancer or ovarian cancer Inclusion:
1.

Jewish (self-report )

2.

attended more than one appointment and observed for at least a year

3.

family history of ovarian cancer (any age) or breast cancer (younger than 50 years) in a 1st or 2nd degree relative

4.

aged 35 or older

USAJewishCohortActual risk: method for calculating risk: survival analysis1st or 2nd degree relative with a family history of ovarian cancer (any age) or breast cancer (before age 50)290475 eligible, 83 excluded because they had < 1 year follow-up; 290 in analysis. DNA specimens for 213 (73.4%) BRCA1 and BRCA2 Selected mutations: Ashkenazi Jewish panelBloodEntire coding region, if sequencedAge: mean: 44.8; 40.4 for mutation carriersExcess risk of breast and ovarian cancer in Jewish women with a family history of ovarian cancer is largely due to mutations in BRCA1. Intensive surveillance with CA-125 and ultrasound does not seem to be an effective means of diagnosing early stage ovarian cancer in this high-risk cohort.Cancer verified by medical and pathology reviewAshkenazi Jewish founder mutations
Cancer incidence in a population of Jewish women at risk of ovarian cancer Sequencing of coding regions for women with incident breast or ovarian cancer who did not have a Jewish founder mutationGender: 100% womenOnly addresses Jewish founder mutations; small chance that non-carriers had a mutation
Race/ethnicity: Jewish (self-report)Tested: younger, more likely to have ovarian cancer family history, longer follow-up: 7.2± 1.7, compared with 5.3± 2.2 overall
Not tested: more missing family history
Malone et al, 2000143 Prev-COCombines data from two case-control studies: Daling et al, 1994244 and Brinton et al, 1995245 Cancer registryBreast cancer: incident and Prevalent Inclusion:
1.

incident cases of early-onset breast cancer diagnosed before age 45

2.

any race

3.

diagnosed between 1/1/1983 and 12/31/1992

4.

residents of King, Pierce, or Snohomish County in Washington state

5.

women

6.

identified through the Cancer Surveillance System

7.

not selected on basis of family history

USAUnselectedPopulation-based, case-controlPrevalenceDiagnosed before 35 or 45 (two different studies used)2,085 cases; 1st data set: Not clear, but same study used by Langston et al, 1996. Blood collected from 592 cases and 165 controls BRCA1 and BRCA2 Screening with confirmation by sequencing: SSCPBloodEntire coding region, intron-exon boundaries promoter region100% women 96.6% Caucasian, 1% African American, 1.6% Asian/Pacific Islander, 0.3% American Indian/Aleutian, 0.6% “Other” Mutation frequency: Cancer was verified.Frame shift mutations result in premature stop colons, most noted in other high-risk families and listed in BIC.
Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases Prev- CADiagnosed ≤ 45 and 1st-degree relative with breast cancer1,736 controls 2nd data set: 648 cases interviewed; blood collected from 545 (84%); 610 controls interviewed; blood taken from 473 (77.5%)Diagnosed <35, unselected for family history: 9.4%Completeness of mutation is okay, screening. Low participation rate. Survivors less extensive breast cancer.
Diagnosed <45, with breast cancer in 1st-degree relative: 12%.
NOTE: These groups overlap
Modan et al, 2001127 Prev-COGeneral populationOvarian cancer: incident Inclusion: Women pathologically confirmed ovarian cancer or primary peritoneal carcinoma, possibly of ovarian originIsraelJewishCase-controlPrevalenceIntermediate risk: one 1st-degree relative with breast cancer840 cases85% of peritoneal or epithelial ovarian cancer interviewed BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/A Cases: Mutation frequency: Cancer was verified pathologically.Ashkenazi Jewish founder mutations
Parity, oral contraceptives, and the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2 mutation High risk: one 1st-degree relative with ovarian cancer or at least two 1st-degree relatives with breast cancer751 controls75% of those interviewed had genetic test resultsBuccal cells, tumor specimens3.7% <40 yearsCases: 29%Ashkenazi Jewish panel was complete.
67% of controls were interviewed19.4% 40–49Controls: 1.7%5% of cases died before interview; 4% were too sick.
78% of controls interviewed had genetic test results24.4% 50–59Modest bias for cases: no difference in age or ancestry for tested versus not tested.
29% 60–69Those tested were slightly more likely to have breast/ovarian cancer in their family history.
23.5%≥ 70 years
71.5% Ashkenazi Jewish
23% Not Ashkenazi Jewish
5.5% mixed
Controls: matched for age (+/- 2 years)
Moslehi et al, 2000135 Pen & Prev-CAHospitalOvarian cancer; prevalent cases Inclusion: North America and IsraelJewishCase-controlPrevalence Actual risk: Kin-cohort methodFamilial: 1 case of familial ovarian cancer (other than proband) or 2 cases of early-onset breast cancer (< age 50 at diagnosis) in 1st and 2nd degree relatives of proband213 Jewish women with ovarian cancer465 potential case subjects. 80 dead, 98 not able to locate. 33 excluded due to diagnosis other than invasive epithelial ovarian cancer. 254 invited to participate, 213 completed family history questionnaire and 208 provided blood sample (208/254 = 82%). 49 refused to participate. BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/ACase: women with ovarian cancer. Mean age at time of interview: 61.2 years (21 – 90). Founder mutation frequency: Cases: 41%Cancer verified through probands, presumably.Ashkenazi Jewish founder mutations
BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer Cases: Jewish women with ovarian cancer in 11 hospitals, and subjects identified through the Ontario Cancer Registry as part of genetics study.Relative Risk: comparison group was part of the study386 Ashkenazi Jewish women without ovarian or breast cancer Cumulative ovarian cancer risk to age 75: Good completeness of mutations—most mutations are founder mutations in this paper. Low participation rate. Survivor bias.
Controls: Jewish women with no history of breast or ovarian cancer recruited from staff of 7 participating hospitals or invited from membership lists of a synagogue and Jewish women's group.1st-degree relatives of cases: 6.3%
1st-degree relatives of controls: 2.0%
Newman et al, 1998145 Prev-CAWomen in Carolina Breast Cancer StudyConducted at homeBreast cancer: incident Inclusion: Women aged 20–74 at diagnosisUSAUnselectedCase-controlPrevalenceHigh risk- 4 or more affected family members, including the proband211 cases77% cases interviewed BRCA1 Selected mutations: 8 specific mutationsBloodEntire coding region56% Caucasian Estimated mutation frequencies: Cancer was verified.Protein truncating [Intron 5 splicing mutation—leads to aberrant mRNA, seen in other high-risk families; nonsense mutation—causes immediate stop in translation at codon 780]
Frequency of breast cancer attributable BRCA1 in a population-based series of American women No cancer188 controls68% controls interviewedScreening with confirmation by sequencing: protein truncation test—exon 11, multiplex SSCASplice junctions and neighboring intronic regions41% African American3.3% white women with breast cancerCompleteness of mutation is okay, screening and common European mutations. Moderate participation rate—no comparison of participants and non-participants. No evidence of bias.
Blood sample taken from 95% of interviewed5′ and 3′ untranslated regions36% between 40–49 years0% black women with breast cancer
27% between 60–74 years23% white women with breast cancer and family history of ovarian cancer
13% white women with breast cancer and high risk, but no ovarian cancer
33% white women with breast cancer and family history of breast/ovarian cancer
Oddoux et al, 1996128 Prev-COHeterozygote detection from autosomol recessive conditionsBreast cancer: prevalent Inclusion: Men and womenUSAAshkenazi and non-Jewish individualsConvenience samplePrevalenceBreast or ovarian cancer in a first or second degree relative—for breast cancer cases only (Memorial Sloan-Kettering Cancer Center)1,255 Ashkenazi JewishNot reported BRCA2 Selected mutations: BRCA2 6174delTBloodN/ANot reportedFindings suggest a difference in cumulative lifetime prevalence for BRCA1 and BRCA2 in Ashkenazi persons. Genetic counseling should be tailored to reflect different risks of the two mutations.Verification of cancer was not reported.Ashkenazi Jewish founder mutations
The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1% Prev- CAGeneral reproductive population519 non-Ashkenazi JewishComplete identification of Ashkenazi Jewish BRCA2 founder mutation.
Cases: 107 with breast/ovarian cancer family historyParticipation rate was not reported.
Possible survivor bias for cases, no information available for controls.
Peto et al, 199929 Prev-CAU.K. National Case Control Study GroupCancer RegistryBreast cancer: prevalent Inclusion:
1.

women diagnosed before age 36 years Or

2.

women diagnosed between 36 and 45 years

EnglandUnselectedCase-controlPrevalenceA mother or sister affected with breast cancer before the age of 60 years6171,399 original sample 44% analyzed BRCA1 and BRCA2 Screening with confirmation by sequencing: CSGEBloodEntire coding region Splice-site junctions41% diagnosed <36Mutations in BRCA1 and BRCA2 genes make equal contributions to early-onset breast cancer, and account for a small proportion of familial breast cancer risk.Cancer was verified. Sensitivity of test estimated at 63%. Low participation rate. Possible survivor bias.Predicted to encode truncated proteins
Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer 59% diagnosed 36–45
Risch et al, 2001133 Pen & Prev-CACancer registryOvarian cancer: incident Inclusion:
1.

women

2.

aged 20–79 at diagnosis

3.

Ontario resident at diagnosis

CanadaUnselectedCase seriesPrevalence Actual risk: method for calculating risk: kin-cohort method (Wacholder et al, 1998246)Risk level: potential familiarity Definition: 1st degree ovarian or breast cancer and < 60 years old649 peopleGroup description: tested Participation rate: 63% total group BRCA1 and BRCA2 Combination of methods:Selected mutations Ashkenazi Jewish panel and other with 11 mutations totalN/AEntire coding regionNot reportedNo mutations found in women with tumors of borderline histology. Mutation frequency among women with invasive cancers was 12% BRCA1 mutation carriers: penetrance by age 80=36% for ovarian cancer and 68% for breast cancer. For BRCA2 mutations, excess of breast cancer was observed only for mutations outside of the ovarian cancer-cluster region (OCCR).Participation rate: 63%All identified mutations deleterious, founder mutations, PTT—mutations associated with shortened, nonfunctional proteins, DGGE—all previously seen, and known to be deleterious (BIC database)
Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer Relative risk: comparison group for relative risk: part of the study OR 375 non-participants: 197 deaths, 76 refused, 57 too ill, 5 MD refused, 8 lost Screening with confirmation by sequencing protein truncation test (PTT) and DGGE (fluorescent multiplex denaturing gradient gel electrophoresis)Intron-exon boundariesEvidence of bias: Survivor bias? 19% eligible cases deceased
2 1st- or 2nd-degree relatives with breast or ovarian cancerFamily history not confirmed
Roa et al, 199612 Prev-CoScreening population for conditions common among Ashkenazi JewsReproductive age population Inclusion: Women and menIsraelAshkenazi JewishConvenience samplePrevalence Relative risk: comparison group was based on attributable risk and mutation frequency estimatorNone3,116Not reported BRCA1 and BRCA2 Selected mutations: Ashkenazi Jewish panel C61G, 4184 del TCAA (BRCA1)BloodN/ANot reported BRCA1 185 del Ag (1.1%) and BRCA2 6174 del T (1.5%) mutations are the second most common mutations predisposing to breast cancer among Ashkenazi Jews.Ashkenazi Jewish panel good, participation rate not reported. Possible bias with reproductive age population.Ashkenazi Jewish founder mutations
Ashkenazi Jewish population frequencies fro common mutations in BRCA1 and BRCA2
Robson et al, 1998153 Prev-CAOffit, 1996247; Neuhausen et al, 199613; Oddoux et al, 1996127 Cancer centerBreast cancer: prevalent Inclusion:
1.

diagnosed with breast cancer before age 42

2.

participated in studies at Memorial Sloan-Kettering Cancer Center between January 1992 and December 1995

3.

Jewish ancestry

USAJewishCase seriesPrevalenceBreast or ovarian cancer in at least 1 1st- or 2nd-degree relative9191 tested Complete BRCA1 testing in 64 cases; 4 underwent targeted sequencing testing; 7 withdrew from study; 12 lost to attrition; 79 completed testing for BRCA2 BRCA1 and BRCA2 Sequencing and Ashkenazi Jewish panelBloodEntire coding region and intron-exon boundaries for those sequenced100% Jewish women. Mutation frequency: Overall: 33%Cancer was verified.Ashkenazi Jewish founder mutations.
BRCA-associated breast cancer in young women Median age at diagnosis = 36 years (range 21–42)Ashkenazi panel and sequencing—good. Original participation rate not reported. Possible survivor biasPremature truncation of the protein product (BRCA2 9325insA)
Satagopan et al, 2001137 Pen & Prev-COControl population obtained via Struewing et al. 199711 3 hospitals and a large series of unaffected survey participantsBreast cancer - incident and a large series of unaffected participants Inclusion: womenUSA & CanadaSelf-identified as JewishCase-controlPrevalence Actual risk: case-control data combined with population incidence ratesCases were unselected for family history of breast cancer782 cases Cases: 900 met inclusion criteria. 782 were analyzed (87%). BRCA 1 and BRCA2 Selected mutations: Ashkenazi Jewish panelStored tissue samples and archival tissuesN/AAge at diagnosis BRCA1: Relative risk of breast cancer estimated 21.6 in women < 40, 9.6 in those aged 40–49, and 7.6 in women ≥ 50. Penetrance of breast cancer at age 70 among BRCA1 mutation carriers: 46% (95% confidence, 31–80%) rising to 59% (95% confidence, 40–93%) at age 80. Control selection: Volunteers from public advertisements, not population-based; different geographic area than casesAshkenazi Jewish founder mutations
The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations Prev-CA Cases:
2.

clinical records of all incident cases of breast cancer between 1980-1995.

3.

women who self-identified as Jewish

4.

received breast-conserving therapy

5.

diagnosed on or before age 65

Relative risk: comparison group was part of the study3,434 controls Controls: 3,434 At the three centers participation was as follows: 78% Memorial Sloan-Kettering Cancer Center 100% Sir Mortimer B. Davis Jewish General Hospital 90% Mount Sinai Medical Center Cases: 64% age 50 +, 26% age 40–49, 9% < age 40. BRCA2: Relative risks in same three age categories estimated to be 3.3, 3.3, and 4.6, respectively, with a penetrance at age 70 of 26% (95% confidence, 14–50%), rising to 38% (95% confidence, 20–68%) at age 80. Lifetime risk of breast cancer in Jewish women who are mutation carriers estimated with this approach is substantially lower than reported estimates using multiple-case families. Risks appear to be different for carriers of BRCA1 and BRCA2 mutations. Case selection:Hospital-based
Controls:
1.

self-identified as Jewish

2.

no previous breast or ovarian cancer

Controls: 47% age 50+, 26% age 40–49; 20% < 40 years
Satagopan et al, 2002136 PenHospital General populationOvarian cancer: incident (series 1) and prevalent (series 2) Controls had no cancer. Inclusion: WomenUSA & IsraelAshkenazi Jewish—series 1 Jewish—series 2 and controlsCase-controlPrevalence Actual risk: case-control data combined with population incidence ratesNot reported382 casesNot reported BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/A100% women Lifetime penetrance: BRCA1: lower than estimates obtained using family data of multiple affected members, but larger than estimates from some population-based proband series Control selection: Volunteers from public advertisements, not population based; different geographic area than casesAshkenazi Jewish founder mutations
Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations Exclusion: Personal history of breast cancerRelative risk: comparison group was part of the study3,434 controlsArchival tissue BRCA2: in the range reported by some family studies Case selection: Hospital based
Stratton et al, 1997147 Prev-CAHospitalOvarian cancer: incident, prevalent Inclusion:
1.

women

2.

diagnosed < 70 years of age

London, EnglandUnselectedCase seriesPrevalenceN/A386 people; 374 = DNA amplification OKGroup description: ovarian cancer cases BRCA1 Screening with confirmation by sequencing: MHABloodEntire coding regionAge: mean or median NS, range NSAssuming lab test sensitivity of 70%, BRCA1 mutations occur in 5% (95% CI: 3–18%) of women diagnosed with ovarian cancer before age 70.Cancer verified: yes, histopathologyPredicted to result in a truncated protein. Novel variant (314 del GAT), resulted in frame detection adjacent to the ring-finger domain—occurred at residue conserved in both mice and humans
Contribution of BRCA1 mutations to ovarian cancer General population Exclusion:
1.

men

2.

≥ age 70 at diagnosis

Participation rate: 80% contacted, 80% total groupIntron-exon boundariesDiagnosis and ages: <40 10%, 40–49 22%, 50–59 41%, 60–69 27%.Completeness of mutation identification: est. 70% sensitivity
Gender: 100% womenParticipation rate: very good 80%
Race/ethnicity: NSEvidence of bias: yes, includes incident and prevalent cases
Struewing et al, 1995126 Prev-COGeneral populationReproductive age, unselected for personal or family cancer history Inclusion: Women and menUSA & IsraelAshkenazi JewishConvenience samplePrevalenceN/A858Not reported BRCA 1 Selected mutations: Ashkenazi Jewish panelBloodN/ANot reported1 in 100 women of Ashkenazi Jewish descent may be at especially high risk of developing breast/ovarian cancer. BRCA1 only 185 del AG, subset only for 5382 ins C.Ashkenazi Jewish founder mutations
The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals Genetic screening for cystic fibrosis and Tay-SachsParticipation rate not reported.
Struewing et al, 199711 Pen & Prev-COGeneral population convenience sampleConvenience sample Inclusion: > 20 years of ageUSAJewishFamiliesPrevalence1st-degree relative with breast/ovarian cancer5,331 individuals7 excluded because of adoption BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/AAge: mean NS 29% 40–49, 24% 50–59Over 2% of Ashkenazi Jews have a BRCA1 or BRCA2mutation that increases breast and ovarian cancer risk. Risk of breast cancer among this population of mutation carriers is 33% by age 50 and 56% by age 70. These are lower than prior estimates. Risk of ovarian cancer among the same group was 16% by age 70.Ashkenazi Jewish panel good, Convenience sample: higher risk individuals may have volunteered.Ashkenazi Jewish founder mutations
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews Prev-CA6 excluded for other reasonsGender: 70% women
Race/ethnicity: 100% Ashkenazi Jewish
Sutcliffe et al, 2000146 Prev-CaUKCCCRCancer registryFamilies with at least two 1st-degree relatives with ovarian cancer Inclusion:
1.

1st-degree female relatives of family members who have ovarian cancer or breast cancer before age 50; all breast/ovarian cancer cases

2.

participated in UKCCCR Familial Ovarian Cancer Registry

3.

registered in January 1991 or later

UKWomen from England and WalesFamiliesPrevalenceRisk determined by number of 1st- or 2nd-degree relatives with breast or ovarian cancer.112 familiesN/A BRCA1 and BRCA2 Screening with confirmation by sequencing: protein truncation test and SSCA/HABloodEntire coding region100% women Relative risks given, but not demographics for age Mutation frequency: Ovarian cancer: 49%Cancer confirmed by histology, death certificate, cancer registry, medical records. Screening for coding regions good.Predicted to result in premature truncation of BRCA1 protein.
Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer Familial OvarianScreening only: specific duplication ( BRCA1)Breast cancer: 49%Participation rate can't be evaluated.Expected to affect splicing, predicted to abolish highly conserved splice-site consensus sequences.
Cancer RegistryBias can't be evaluated. BRCA1 Pro 1749Arg—functional studies suggest that it's functionally significant.
BRCA2 pathogenic mutations: frame shift deletion, nonsense mutation.
Warner et al, 1999138 Prev-CAOncology centers in Toronto and MontrealBreast cancer: prevalent Case Inclusion:
1.

living

2.

Jewish

3.

women

4.

unselected age

5.

diagnosed with invasive breast cancer before 5/1/1998

6.

followed at 1 of 6 oncology centers in Toronto or Montreal

Canada & USAAshkenazi Jewish for cases and controlsCase-control FamiliesPrevalence Actual risk: Kin-cohort method1st-, 2nd-, or 3rd-degree relatives with breast or ovarian cancer412 Jewish breast cancer cases700 contacted and 457 (65.3%) agreed to participate; 412 (90%) had genetic testing BRCA1 and BRCA2 Ashkenazi Jewish panelBloodN/AAge: mean 61.1 for cases; 59.1 for non-Jewish controls; 52.6 for Jewish controls.Mutation prevalence: 11.7%Cancer was verified through pathology records for cases.Ashkenazi Jewish founder mutations
Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer No cancer Cases Exclusion:
1.

Sephardic

2.

converted to Judaism

3.

adopted

Non-Jewish with breast cancer48 1st-degree relatives of mutation positive cases360 non-Jewish controls with breast cancer; and 380 Jewish control without breast cancerMean age at diagnosis: 54.3 for Jewish breast cancer cases; 53.2 for non-Jewish breast cancer cases Estimated penetrance to age 70 for breast cancer: Ashkenazi Jewish panel only.
Control Patients Inclusion:
1.

non-Jewish women

2.

with breast cancer

Gender: 100% women BRCA1 gene mutations: 59.9%Modest participation rate, participants and non-participants were not compared.
Control Subjects Inclusion:
1.

Jewish women

2.

aged 25–88

3.

without breast cancer

BRCA2 gene mutations: 28.3%Possible survivor bias.
Control Exclusion:
1.

history of breast or ovarian cancer

2.

Sephardic

3.

converted to Judaism

4.

adopted

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