# Inherited risk is mostly unidentified

Source: https://onco.cc/bottlenecks/b-hereditary-risk/  
OnCo record `b-hereditary-risk` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Most people who carry a high-risk cancer gene do not know it until they or a relative gets cancer.

## Summary

Pathogenic germline variants in BRCA1/2, the Lynch syndrome mismatch-repair genes, TP53, PALB2, CDH1 and others confer lifetime cancer risks of 40-80%, and effective risk reduction exists (risk-reducing surgery, intensified surveillance, aspirin, PARP inhibitors when cancer occurs). Yet most carriers are identified only after a cancer diagnosis, and often not even then: fewer than a fifth of US women with a history of breast or ovarian cancer who met testing criteria had been tested. Cascade testing of relatives, the cheapest way to find healthy carriers, reaches a minority of eligible family members. Germline testing is also inequitable, with reference databases dominated by European ancestry, so variants of uncertain significance are more common in other populations. Polygenic risk scores could stratify screening for common cancers but are not yet implemented or validated across ancestries.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: prevention-detection
- Severity: major
- Metrics: US women with a history of breast or ovarian cancer meeting NCCN criteria who had undergone genetic testing (2005-2015 NHIS): Fewer than 20% (Childers et al., JCO 2017); Estimated population prevalence of Lynch syndrome: About 1 in 279 (Win et al., Cancer Epidemiology, Biomarkers & Prevention 2017); Share of participants in genome-wide association studies of European ancestry (2016): 81% (Popejoy & Fullerton, Nature 2016)
- Causes: Testing is triggered by family history, which is often unknown, incomplete or not asked about.; Cascade testing depends on the index patient informing relatives, with no systematic follow-through.; Genetic counselling capacity is limited and testing criteria are complex.; Reference databases under-represent non-European ancestries, producing more uncertain variants.; Population screening for germline variants has been considered too costly, although sequencing costs have fallen sharply.

## Sources

- Childers et al., National estimates of genetic testing in women with breast or ovarian cancer (JCO 2017): https://doi.org/10.1200/JCO.2017.73.6314
- Win et al., Prevalence and penetrance of major genes for colorectal cancer (CEBP 2017): https://doi.org/10.1158/1055-9965.EPI-16-0693
- ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/

## Connected records

- collections: [ClinVar](https://onco.cc/collections/clinvar/)
- ideas: [A bone drug to prevent breast cancer in BRCA1 carriers](https://onco.cc/ideas/idea-prev-brca1-denosumab-prevention/), [A chatbot for pre-test genetic counselling so counsellors see only who needs them](https://onco.cc/ideas/idea-prev-genetic-counselling-chatbot/), [A frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval](https://onco.cc/ideas/idea-moon-lynch-vaccine-phase3/), [A randomised trial of a shared-antigen vaccine to prevent Lynch syndrome cancers](https://onco.cc/ideas/idea-prev-lynch-frameshift-vaccine-rct/), [A UK audit of trial access and germline testing uptake in triple-negative breast cancer](https://onco.cc/ideas/idea-tnbc-uk-trial-access-and-germline-testing-audit/), [Automatic germline testing for every cancer type where it changes care](https://onco.cc/ideas/idea-prev-reflex-germline-testing/), [Ban life and disability insurers from using genetic results](https://onco.cc/ideas/idea-prev-genetic-non-discrimination-insurance/), [Build polygenic scores that work in every ancestry before deploying any](https://onco.cc/ideas/idea-prev-prs-ancestry-portability-standard/), [Cancer interception vaccines for high-risk carriers](https://onco.cc/ideas/idea-interception-vaccines/), [Engineered immune surveillance: long-lived programmed immune cells that patrol for early cancer](https://onco.cc/ideas/idea-moon-engineered-immune-surveillance/), [Family history collected by app and matched to testing criteria automatically](https://onco.cc/ideas/idea-prev-family-history-auto-match/), [Get every Lynch syndrome carrier onto the right dose of aspirin](https://onco.cc/ideas/idea-prev-lynch-aspirin-implementation/), [Go back to families of women who died of ovarian cancer and offer BRCA testing](https://onco.cc/ideas/idea-prev-traceback-deceased-probands/), [Let clinics contact relatives directly when a cancer gene is found](https://onco.cc/ideas/idea-prev-cascade-direct-contact-relatives/), [Offer everyone at 30 a test for the cancer genes that matter](https://onco.cc/ideas/idea-prev-population-germline-screening-at-30/), [Oncology teams order germline tests; tele-genetic counsellors handle the results](https://onco.cc/ideas/idea-acc-mainstream-tele-genetic-counselling/), [Population germline screening for hereditary cancer genes with cascade testing](https://onco.cc/ideas/idea-moon-population-germline-screening/), [Store adult-onset cancer gene results from newborn genomes and disclose at 18](https://onco.cc/ideas/idea-prev-deferred-disclosure-newborn-genomes/), [Surveillance for every germline carrier found by universal testing, inside a registry rather than a research exception](https://onco.cc/ideas/idea-pdac-surveillance-for-every-germline-carrier/), [Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later](https://onco.cc/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/), [Test every possible mutation in every cancer gene so no result is 'uncertain'](https://onco.cc/ideas/idea-prev-vus-saturation-editing-consortium/), [Universal tumour and germline sequencing at diagnosis feeding a shared learning system](https://onco.cc/ideas/idea-moon-universal-sequencing-learning-system/), [Use a polygenic risk score to set when screening starts](https://onco.cc/ideas/idea-prev-prs-screening-start-age/), [Whole-body MRI plus blood DNA surveillance for people with Li-Fraumeni syndrome](https://onco.cc/ideas/idea-prev-li-fraumeni-mri-plus-cfdna/)
- cancers: [Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours)](https://onco.cc/cancers/pleuropulmonary-blastoma/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Endometrial cancer](https://onco.cc/cancers/endometrial/), [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [HR-positive / HER2-negative breast cancer](https://onco.cc/cancers/breast-hr-positive/), [Male breast cancer](https://onco.cc/cancers/male-breast-cancer/), [Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)](https://onco.cc/cancers/multiple-endocrine-neoplasia/), [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- technologies: [Chemoprevention & risk-reducing surgery](https://onco.cc/technologies/chemoprevention/), [Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)](https://onco.cc/technologies/colorectal-screening/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Risk-reducing and opportunistic salpingectomy](https://onco.cc/technologies/risk-reducing-salpingectomy/), [Second cancers after childhood cancer: the risk by treatment, and why it is falling](https://onco.cc/technologies/rejuv-paed-second-cancers/)
- targets: [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Olaparib](https://onco.cc/drugs/olaparib/)
- companies: [Illumina](https://onco.cc/companies/illumina/), [Natera](https://onco.cc/companies/natera/)
- terms: [Age, smoking and inherited predisposition: what the treatment risk is added to](https://onco.cc/terms/rejuv-second-age-smoking-and-inherited-risk/), [Association for Molecular Pathology v. Myriad Genetics (2013)](https://onco.cc/terms/myriad-ruling/), [Founder variant](https://onco.cc/terms/founder-variant/), [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [GINA (Genetic Information Nondiscrimination Act 2008)](https://onco.cc/terms/gina/), [Homologous recombination deficiency (HRD)](https://onco.cc/terms/hrd/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [MEN1 and hereditary neuroendocrine syndromes](https://onco.cc/terms/men1-hereditary-net/), [Polygenic risk score (PRS)](https://onco.cc/terms/polygenic-risk-score/), [Variant of uncertain significance (VUS)](https://onco.cc/terms/vus/)
- trials: [OlympiA](https://onco.cc/trials/olympia/)
- key papers: [Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer](https://onco.cc/key-papers/paper-hu-germline-mutations-pancreatic-cancer-risk-jama-2018/), [CAPP2: two years of aspirin cuts bowel cancer in Lynch syndrome by more than a third over 10 years](https://onco.cc/key-papers/paper-capp2-aspirin-lynch-lancet-2020/), [Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer](https://onco.cc/key-papers/paper-atchley-brca-status-triple-negative-jco-2008/), [First trial of a vaccine against the shared neoantigens of mismatch-repair-deficient cancers](https://onco.cc/key-papers/paper-lynch-frameshift-vaccine-ccr-2020/), [Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer](https://onco.cc/key-papers/paper-gorski-brca1-founder-mutations-poland-ajhg-2000/), [IBIS-I: five years of tamoxifen keeps preventing breast cancer for at least 20 years](https://onco.cc/key-papers/paper-ibis-i-tamoxifen-lancet-oncol-2015/), [Inherited DNA-repair gene mutations in men with metastatic prostate cancer](https://onco.cc/key-papers/paper-pritchard-inherited-dna-repair-metastatic-prostate-nejm-2016/), [Management of Hereditary Breast Cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline](https://onco.cc/key-papers/paper-asco-hereditary-breast-cancer-guideline-jco-2020/), [Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium](https://onco.cc/key-papers/paper-caps-consortium-surveillance-recommendations-gut-2020/), [National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer](https://onco.cc/key-papers/paper-childers-j-clin-oncol/), [OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer](https://onco.cc/key-papers/paper-olympia-nejm-2021/), [Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2](https://onco.cc/key-papers/paper-gabai-kapara-population-brca-screening-pnas-2014/), [Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer](https://onco.cc/key-papers/paper-win-cancer-epidemiol-biomarkers-prev/), [PROSE consortium: preventive surgery lowers cancer and death in BRCA1 and BRCA2 carriers](https://onco.cc/key-papers/paper-brca-risk-reducing-surgery-jama-2010/), [Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance](https://onco.cc/key-papers/paper-canto-caps-long-term-surveillance-gastroenterology-2018/), [SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer](https://onco.cc/key-papers/paper-solo-1-nejm-2018/), [SU2C-PCF: integrative clinical genomics of advanced prostate cancer](https://onco.cc/key-papers/paper-robinson-integrative-clinical-genomics-advanced-prostate-cell-2015/), [The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival](https://onco.cc/key-papers/paper-dbouk-caps5-stage-survival-jco-2022/), [The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews](https://onco.cc/key-papers/paper-struewing-brca-founder-mutations-ashkenazi-nejm-1997/), [Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction](https://onco.cc/key-papers/paper-conti-trans-ancestry-gwas-prostate-nat-genet-2021/)
- roadmaps: [Cancer prevention roadmap: tobacco control and vaccines → biomarker-guided chemoprevention → interception in carriers](https://onco.cc/roadmaps/prevention-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Prostate cancer roadmap: from Huggins and the discovery that a cancer can depend on a hormone, through the PSA epidemic and what it cost, the androgen receptor drugs, the DNA repair subset and PSMA, to a 2032 registry watch](https://onco.cc/roadmaps/prostate-roadmap/), [Triple-negative breast cancer roadmap: from a remainder defined by three negative tests to immunotherapy, antibody-drug conjugates and the residual disease problem](https://onco.cc/roadmaps/tnbc-roadmap/)
- people: [Angelina Jolie](https://onco.cc/people/angelina-jolie/), [Eitan Friedman](https://onco.cc/people/eitan-friedman/), [Ephrat Levy-Lahad](https://onco.cc/people/ephrat-levy-lahad/), [Gilda Radner](https://onco.cc/people/gilda-radner/), [Jon M. Huntsman Sr.](https://onco.cc/people/jon-huntsman/), [Mary-Claire King](https://onco.cc/people/mary-claire-king/), [Rachel Michaelson-Cohen](https://onco.cc/people/rachel-michaelson-cohen/)
- institutions: [Fox Chase Cancer Center](https://onco.cc/institutions/fox-chase/), [Hadassah Medical Center](https://onco.cc/institutions/hadassah/), [Huntsman Cancer Institute, University of Utah](https://onco.cc/institutions/huntsman/), [HUS Comprehensive Cancer Center, Helsinki University Hospital](https://onco.cc/institutions/helsinki-hus/), [Instituto Português de Oncologia do Porto Francisco Gentil](https://onco.cc/institutions/ipo-porto/), [Shaare Zedek Medical Center](https://onco.cc/institutions/shaare-zedek/), [The Hospital for Sick Children (SickKids)](https://onco.cc/institutions/sickkids/)

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JSON: https://onco.cc/api/v1/entities/b-hereditary-risk.json