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BRCA1 / BRCA2

BRCA1 and BRCA2 are tumor suppressor genes that help cells repair double-strand DNA breaks using homologous recombination: a precise copy-from-a-template method. Inherited harmful variants raise lifetime risk of breast, ovarian, and other cancers. The risk follows autosomal dominant inheritance (one faulty copy is enough to increase risk), but penetrance is incomplete: not every carrier develops cancer.

Tumor suppressorAutosomal dominantDNA double-strand break repair

Inheritance:

Autosomal dominant cancer predisposition: a heterozygous pathogenic variant (one mutant copy paired with one normal copy) increases lifetime risk without requiring two mutant alleles for the predisposition itself. Tumours often need a second somatic hit to lose function fully in the cancer cell.

Function

BRCA1 and BRCA2 encode proteins that are essential for repairing double-strand DNA breaks: breaks where both strands of the DNA helix are severed. They mainly use homologous recombination (HR), an error-free pathway that copies sequence from a matching sister chromatid (the duplicate chromosome present after DNA replication). These genes act as tumor suppressors, guarding the genome by stopping cells with damaged DNA from dividing. That prevents further genomic instability, a buildup of mutations and broken chromosomes, from accumulating.

Pathogenic variants

Inherited (germline) pathogenic variants, often frameshift, nonsense, or splice-site mutations that disrupt the protein-coding sequence, reduce or abolish protein function. Carriers face elevated lifetime risk of breast, ovarian, prostate, and pancreatic cancer. The risk is high but not 100% because penetrance is incomplete: age, family history, and other genes also influence outcomes. Many tumours need a second hit: an additional mutation in the same gene, to fully disable repair in the cancer cell.

Inheritance pattern

Inheritance is autosomal dominant for cancer predisposition: the variant sits on a non-sex chromosome, and one pathogenic allele is enough to increase risk. That differs from recessive diseases, where two mutant copies are needed for symptoms. Each child of a carrier has a 50% chance of inheriting the variant at each pregnancy. Many carriers remain asymptomatic for years. Enhanced screening (for example MRI alongside mammography), risk-reducing surgery, and lifestyle counselling are discussed in clinical genetics. Decisions depend on personal and family history.

Clinical & research importance

BRCA testing revolutionised hereditary cancer screening by showing that a single monogenic variant can confer a large increase in risk for specific cancers. It also led to targeted therapies: PARP inhibitors that exploit HR deficiency in tumours through synthetic lethality (blocking a backup repair route the cancer now needs). Population screening debates continue for founder mutations in groups such as Ashkenazi Jewish communities, where certain BRCA variants are unusually common because of shared ancestry.

But how do we know?

Researchers first mapped these genes using linkage analysis in high-risk families. Mary-Claire King's group (1990) placed BRCA1 on chromosome 17; BRCA2 was localised to chromosome 13 in 1994, and the gene itself was identified in 1995. Miki et al. (1994) reported the cloned BRCA1 sequence. Sequencing revealed truncating mutations enriched in affected pedigrees. Founder mutations (for example in Ashkenazi Jewish communities) were later identified by genotyping cohorts: evidence built from pedigrees plus DNA, not guesswork.

Key facts

BRCA1 (chr 17) and BRCA2 (chr 13) encode distinct proteins that work together in homologous recombination to repair broken DNA.
Autosomal dominant predisposition: each egg or sperm from a carrier parent has a ~50% chance of carrying the variant through meiosis.
Penetrance is incomplete: not all carriers develop cancer; risk management is personalised to each person.
PARP inhibitors exploit HR deficiency in BRCA-mutant tumours through synthetic lethality: a targeted treatment strategy.

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This story links to meiosis (each gamete has a ~50% chance of carrying the variant) and to molecular genetics, where loss of DNA repair protein function raises mutation rates. It also shows why family history matters in medicine and genetic counselling.

BRCA1 / BRCA2