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. PARP inhibitors are now standard of care for BRCA-associated ovarian and metastatic breast cancers in many guidelines.

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. Risks for contralateral breast cancer and other cancers (pancreatic, prostate) are also elevated.
• Risk-reducing options with established evidence include: enhanced surveillance (annual MRI plus mammography from age 25–30), risk-reducing salpingo-oophorectomy (typically by age 40–45 for BRCA1 carriers, reducing ovarian and 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 (lifetime cancer risk estimates); Miller et al., Genet Med 2023 (ACMG SF v3.2 list including BRCA1); ENIGMA consortium variant curation guidelines.

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 reads your raw file and will surface BRCA1 SNPs that your array genotyped. We do not generate a clinical BRCA1 report. We do consistently route users toward the appropriate resource: a board-certified genetic counsellor, a clinical hereditary-cancer panel, and — where indicated — guideline-based surveillance and risk reduction.