BRCA1

A DNA repair workhorse.

BRCA1 encodes a large multi-domain nuclear protein that functions as a scaffold and regulator in homologous-recombination repair (HRR) — the high-fidelity pathway for repairing DNA double-strand breaks. BRCA1 recruits and stabilizes the partner protein PALB2, which in turn recruits BRCA2 and the recombinase RAD51 to sites of damage. The protein also participates in checkpoint signalling, transcriptional regulation, and chromatin remodelling.

When one BRCA1 allele carries a loss-of-function variant, cells still have a functional copy and behave normally most of the time. The risk arises from the "two-hit" hypothesis articulated by Knudson: somatic loss of the remaining functional allele — by deletion, point mutation, or epigenetic silencing — leaves the cell unable to repair double-strand breaks accurately. Such cells accumulate mutations rapidly and are at high risk of malignant transformation, particularly in tissues with high cell-turnover hormonal exposure (breast and ovarian epithelium).

This same defect is the basis of synthetic-lethal therapy with PARP inhibitors (olaparib, talazoparib, niraparib, rucaparib): these drugs prevent the alternative single-strand-break repair pathway, and cells with deficient HRR cannot survive the resulting unrepaired damage. Their FDA-approved uses differ by drug: olaparib in ovarian, breast, pancreatic and prostate cancer; talazoparib in breast and prostate cancer; niraparib alone (ZEJULA) in ovarian cancer and, combined with abiraterone (AKEEGA), in BRCA-mutated prostate cancer; rucaparib in ovarian and prostate cancer — in each case with patients selected by BRCA, HRR or HRD testing.

Thousands of variants, three commonly genotyped on consumer arrays.

Most BRCA1 pathogenic variants are private to one or a few families. A small number recur at appreciable frequency in specific populations — these are the variants that some direct-to-consumer DNA services explicitly report on (with FDA authorization in the US, and equivalent regulatory oversight elsewhere):

One of the highest-impact actionable findings in genomics.

BRCA1 is on the ACMG Secondary Findings list — the small set of genes where, if a pathogenic variant is discovered incidentally during clinical sequencing, the patient is advised to be informed because actionable preventive measures exist. Specifically:

• Lifetime cancer risk for BRCA1 pathogenic-variant carriers, summarized from large prospective cohorts (Kuchenbaecker et al., JAMA 2017): breast cancer ~72% (95% CI 65–79) by age 80; ovarian cancer ~44% (95% CI 36–53) by age 80. Contralateral breast cancer risk is also elevated, and the NCI lists lifetime risks of up to 5% for pancreatic cancer (about 1.7% in the general population) and about 7–26% by age 80 for prostate cancer (about 10.6% in the general population).
• Risk-reducing options with established evidence include: enhanced surveillance (annual MRI plus mammography from age 25–30), risk-reducing salpingo-oophorectomy (reducing ovarian and possibly breast cancer risk), and risk-reducing bilateral mastectomy.
• Therapeutic implications for already-diagnosed carriers: PARP inhibitor therapy, platinum-based chemotherapy considerations, and informed surgical decisions.
• Cascade testing matters: first-degree relatives have a 50% chance of carrying the same variant, and family communication is part of standard genetic counselling.

Equally important is what BRCA1 testing on a consumer SNP chip cannot do:

• It cannot detect the vast majority of BRCA1 pathogenic variants — only the specific founder variants its probes target.
• A "negative" result on a consumer test is not a clinically negative BRCA1 result. It only means the few variants tested were not detected.
• Consumer-grade arrays have well-documented false-positive rates in rare variants; positive results require confirmation in a clinical laboratory.

Primary sources: ClinVar — BRCA1 entries; OMIM 113705 — BRCA1; Kuchenbaecker et al., JAMA 2017 (breast, ovarian and contralateral breast cancer risk); NCI BRCA fact sheet (pancreatic and prostate risk, risk-reducing surgery); Miller et al., Genet Med 2023 (ACMG SF v3.2 list including BRCA1); Parsons et al., Am J Hum Genet 2024 (ClinGen ENIGMA BRCA1/BRCA2 variant curation specifications); Hashizume et al., J Biol Chem 2001 (C61G and BRCA1–BARD1 ubiquitin ligase); Tandy-Connor et al., Genet Med 2018 (false positives in DTC raw data); FDA De Novo DEN170046 (2018, BRCA1/BRCA2 selected-variants report); FDA labels for LYNPARZA, TALZENNA, ZEJULA and RUBRACA.

Read this before — and after — looking up BRCA1.

Some consumer services, including 23andMe, report on the three Ashkenazi Jewish founder variants (185delAG, 5382insC, and 6174delT — the last is in BRCA2). If you have one of these results, the framing matters:

• A positive result on any of these variants requires confirmation in a clinical laboratory before any clinical decision. Consumer arrays are screening tools, not diagnostic ones.
• A negative result does not rule out BRCA1 pathogenic variants. If you have a family history that concerns you, that is still a reason to seek genetic counselling — your specific family variant may simply not be on the consumer chip.
• Population context matters. The Ashkenazi founder panel is genuinely informative for people of Ashkenazi ancestry. For other populations the same three SNPs have very low prior probability and the test provides almost no information.

DeepDNA is an API for developers and AI agents, not a consumer service: there is no upload form, and we do not generate a clinical BRCA1 report. The endpoint below returns this page’s record as JSON — the variants a consumer array can test, why a negative array result is not a clinical negative, and the sources. The record says what this page says: if your family history worries you, the next step is a genetic counsellor or clinical geneticist and, where indicated, a clinical hereditary-cancer panel, not a consumer chip.