A claim you hear on longevity podcasts
Leaning for. Of 9 studies that test it, 7 partly agree and 2 agree.
The claim checked: BRCA1 means a ninefold to tenfold risk of early breast cancer, and single genes explain only part of family risk Hear it at 18:21
Every study finds a large rise in risk. Two of nine agree with the size said, both across all ages: odds ratios up to 10.57 across high-risk genes, and 7.62 for BRCA1. Seven are mixed, and most of them put the early-age risk much higher. One found a relative risk of 33 at ages 30 to 39. In Malaysia and Singapore it was about 25 before age 30. The risk falls with age.
Computed from 9 studies that test this point, each judged by two readers, in full. 10 more studies are waiting for a full read and do not count yet.
“BRCA1 is a shove mutation. It shoves you off the cliff and puts you at a ninefold, tenfold risk above the normal population to get hereditary breast cancer at an early age.”
trial or observed group · 2021 · landmark
“For these genes, odds ratios ranged from 2.10 to 10.57.”
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med
Who: 60,466 women with breast cancer and 53,461 controls from 44 BCAC studies; risk estimates from population-based studies (48,826 cases, 50,703 controls)
PMID 33471991
trial or observed group · 2021 · landmark
“In the population-based studies, BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% CI, 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively (Table 2 and Table S10).”
A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med
Who: 32,247 women with breast cancer and 32,544 unaffected women from 12 US population-based studies (CARRIERS), mean age about 62
PMID 33471974
pooled analysis · 2003 · landmark
“For BRCA1, the breast cancer RR increased to 33 in the 30–39-years age group and decreased with age thereafter (P trend .012), whereas the ovarian cancer RR estimates showed no apparent trend with age.”
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
Who: 8,139 index cases with breast (female 86%, male 2%) or ovarian (12%) cancer unselected for family history, from 22 studies; penetrance estimated from first-degree relatives of 500 BRCA1/BRCA2 mutation carriers (280 BRCA1 families analysed)
PMID 12677558
other primary study · 2017 · landmark
“The breast cancer SIRs decreased with increasing age for both BRCA1 and BRCA2 carriers, but the estimates were higher than those previously reported for younger age groups.”
Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA
Who: 9,856 female BRCA1/2 carriers (6,036 BRCA1) recruited 1997-2011 through IBCCS, BCFR and kConFab, 94% via family clinics; breast cancer analysis in 3,886 cancer-free women (2,276 BRCA1)
PMID 28632866
other primary study · 2006
“The incidence was significantly higher among BRCA1 and BRCA2 carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; P < 0.001) and amongst subjects classified at high (SIR = 4.5; 95% CI = 1.5 to 8.3; P < 0.001) or intermediate risk (SIR = 7.0, 95% CI = 2.0 to 17.1; P = 0.0018).”
Breast cancer screening in women at increased risk according to different family histories: an update of the Modena Study Group experience. BMC Cancer
Who: 1,325 asymptomatic women from high-risk families in an Italian surveillance program, of whom 48 were BRCA1/2 carriers (37 BRCA1, 11 BRCA2)
PMID 16916448
other primary study · 2024
“Our study showed that breast cancer RRs vary substantially by age, from approximately 25 for BRCA1 and 10 for BRCA2 at age <30 to 10 for BRCA1 and 5 for BRCA2 at age >70.”
Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families. Lancet Reg Health West Pac
Who: 572 families from Malaysia and Singapore with BRCA1 (271) or BRCA2 (301) pathogenic variants, mostly from case series unselected for family history; 1,121 female first-degree relatives in BRCA1 families
PMID 38333895
other primary study · 2000 · landmark
“The relative risk of breast cancer for BRCA1 mutation carriers decreased with age, but for BRCA2 mutation carriers the relative risk for the three age-groups varied little.”
Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Anglian Breast Cancer Study Group. Br J Cancer
Who: 1,435 women diagnosed with breast cancer before age 55 in East Anglia (population-based), effective sample 1,220 after PCR failure; 8 BRCA1 and 16 BRCA2 carriers
PMID 11044354
other primary study · 2025
“Compared to non-carriers, the most rapid increase in breast cancer penetrance among BRCA1 P/LP variant carriers occurred around the age of 35 years, with a cumulative risk ratio of 29.85, which then leveled off and reached a cumulative risk ratio of 4.02 at 85 years.”
Breast cancer risk associated with BRCA1 and BRCA2 pathogenic variants in the Eastern Chinese population. Cancer Pathog Ther
Who: 2,216 community breast cancer survivors in Eastern China (Jiangsu, Zhejiang, Shanghai), 49 BRCA1 and 60 BRCA2 carriers; kin-cohort analysis of 13,957 first-degree relatives
PMID 40182128
pooled analysis · 2025
“Gene-based association tests revealed that BRCA1 , BRCA2 and PALB2 PV carriers had a significantly elevated risk of BC ( Table 2 ), while ATM PV carriers showed a nominal association with BC risk.”
Impact of germline variants on breast and ovarian cancer risk in Japanese women: an original cohort study and meta-analysis. EBioMedicine
Who: 7,220 Japanese women with breast cancer and 4,032 cancer-free female controls from hospital registries (original cohort), plus a meta-analysis with 6 prior Japanese studies
PMID 40403695
Two of ten studies agree: known genes explain less than 25% of family risk, and many genes of small effect may explain the rest. Eight are mixed. The common variants found so far explain only about 18% of family risk, and all common variants together at best about 41%. Much of family risk is still unexplained.
Computed from 10 studies that test this point, each judged by two readers, in full. 4 more studies are waiting for a full read and do not count yet.
other primary study · 2007 · landmark
“Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks.”
Genome-wide association study identifies novel breast cancer susceptibility loci. Nature
Who: women of European and Asian ancestry with breast cancer and controls: stage 1 390 familial cases and 364 controls (UK), stage 2 3,990 cases and 3,916 controls (SEARCH), stage 3 21,860 invasive cases and 22,578 controls from 22 studies
PMID 17529967
other primary study · 2002 · landmark
“The polygenic model suggests that several genes, each having small but multiplicative effects on risk can account for the residual non-BRCA1/2 familial clustering of breast cancer.”
A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer
Who: Combined UK dataset: population-based Anglian Breast Cancer study cases diagnosed under age 55 plus 156 UK multiple-case breast cancer families, with BRCA1/BRCA2 mutation screening
PMID 11857015
other primary study · 2022
“As illustrated in Figure 1 , there is substantial breast cancer familial variance that cannot be explained by the known susceptibility genes and common genetic variants, and the unexplained familial variance is larger at younger ages.”
Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction. Am J Hum Genet
Who: 17,425 three-generation families ascertained via population-based breast cancer probands in Australia (ABCFR, 2,712) and the UK (SEARCH, 14,713), mostly White European; complex segregation analysis
PMID 36206742
other primary study · 2017 · landmark
“We estimate that the newly identified susceptibility loci explain ˜4% of the two-fold familial relative risk (FRR) of breast cancer and that in total, common susceptibility variants identified through GWAS explain 18% of the FRR.”
Association analysis identifies 65 new breast cancer risk loci. Nature
Who: 61,282 female breast cancer cases and 45,494 controls of European ancestry (OncoArray, BCAC and DRIVE), meta-analysed with iCOGS and 11 other GWAS
PMID 29059683
other primary study · 2013 · landmark
“When taking into account effects from the previously known loci, these analyses suggest that ~28% of familial risk is explained by common variants selected for iCOGS, of which ~14% can be explained by the 67 established loci (with a further ~20% due to higher penetrance loci).”
Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet
Who: women of European ancestry: 10,052 cases and 12,575 controls from 9 GWAS, then 45,290 cases and 41,880 controls from 41 BCAC studies genotyped on iCOGS
PMID 23535729
other primary study · 2019 · landmark
“We previously estimated using GWAS data that the theoretically best PRS, if the effect sizes of all common SNPs were known with certainty, would explain ∼41% of the familial risk of breast cancer, corresponding to a standardized OR∼2.1: the PRS 313 explains ∼45% of this “chip” heritability.”
Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. Am J Hum Genet
Who: 94,075 breast cancer cases and 75,017 controls of European ancestry from 69 BCAC studies for PRS development; validated in 11,428 cases and 18,323 controls from 10 prospective cohorts and 190,040 UK Biobank women
PMID 30554720
pooled analysis · 2015 · landmark
“Taken together with previously identified loci, more than 90 independent common susceptibility loci for breast cancer have been identified, explaining ~16% of the familial risk.”
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet
Who: women of European ancestry: 15,748 breast cancer cases and 18,084 controls from 11 GWAS plus 46,785 cases and 42,892 controls from 41 iCOGS studies
PMID 25751625
pooled analysis · 2020 · landmark
“These 210 variants explained approximately 18.3% of the two-fold familial relative risk for invasive breast cancer, while all reliably imputable variants on the OncoArray explained 37.1% ( Online Methods ).”
Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet
Who: Women of European ancestry: 118,474 cases and 96,201 controls from 82 BCAC studies plus summary data from 11 other GWAS, and 9,414 affected and 9,494 unaffected BRCA1 mutation carriers from 60 CIMBA studies
PMID 32424353
other primary study · 2015 · landmark
“This attenuation (~12.6%) was consistent with the estimated fraction of the two-fold FRR explained by the 77-SNPs under a polygenic risk model ( 15 ).”
Prediction of breast cancer risk based on profiling with common genetic variants. J Natl Cancer Inst
Who: Women of European origin in 41 Breast Cancer Association Consortium studies (Europe, North America, Australia); PRS analyses excluded studies that oversampled family-history cases
PMID 25855707
other primary study · 2018
“We believe it might be reasonable to interpret the findings that common variants explain as much Σ%FRR of high-risk cancers as BRCA1/2 mutations.”
BRCA1/2-negative, high-risk breast cancers (BRCAX) for Asian women: genetic susceptibility loci and their potential impacts. Sci Rep
Who: Korean women with high-risk breast cancer who tested negative for BRCA1/2 mutations (KOHBRA study) vs Korean controls (KoGES), replicated in Asian and European high-risk cases from the Breast Cancer Association Consortium
PMID 30323354
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