Familial breast cancer: BRCA1, BRCA2 and others

Mechanism

A minority of breast cancers come from an inherited faulty gene, most often BRCA1 or BRCA2; they start younger, can affect both breasts and run in families.

Updated Nov 12, 2026

Key points

Clues to a hereditary cause: young age at diagnosis, bilateral or multiple primaries, male breast cancer, ovarian cancer in the family, several affected relatives, triple-negative cancer in a young woman.
BRCA1 (chromosome 17q21): high lifetime risk of breast and ovarian cancer; tumours are often triple-negative, basal-like, high grade, with medullary features.
BRCA2 (chromosome 13q12): breast (including male), ovarian, prostate and pancreatic cancer and melanoma; tumours usually ER-positive.
TP53 (Li-Fraumeni): very early breast cancer, often HER2-positive, with sarcomas, brain and adrenal tumours.
PTEN (Cowden): breast, thyroid and endometrial cancer and hamartomas; CDH1: lobular breast cancer and diffuse gastric cancer.
BRCA-deficient cancers are sensitive to platinum and PARP inhibitors (synthetic lethality).

What it is

About one in ten breast cancers is caused by an inherited mutation in a single gene. BRCA1 and BRCA2, which repair DNA double-strand breaks by homologous recombination, account for the largest share; carriers inherit one faulty copy, and tumours arise when the second copy is lost. Other high-risk genes are TP53 (Li-Fraumeni syndrome), PTEN (Cowden syndrome), CDH1 (hereditary diffuse gastric cancer with lobular breast cancer), STK11 and PALB2, while CHEK2 and ATM add moderate risk. BRCA1 cancers are usually triple-negative and basal-like; BRCA2 cancers are usually ER-positive.

Step by step

A person inherits one mutated copy of a DNA repair gene such as BRCA1 or BRCA2 (first hit, in every cell).
In a breast epithelial cell, the normal copy is lost (second hit).
Without homologous recombination, double-strand breaks are repaired by error-prone pathways.
Genomic instability accumulates, often with TP53 loss, and a cancer develops at a younger age than usual.
Because every cell carries the first hit, both breasts and other organs (ovary, prostate, pancreas) are at risk.

High- and moderate-risk breast cancer genes

Gene	Syndrome	Other cancers	Typical breast tumour
BRCA1	Hereditary breast and ovarian cancer	Ovary, tube	Triple-negative, basal-like
BRCA2	Hereditary breast and ovarian cancer	Ovary, male breast, prostate, pancreas, melanoma	ER-positive
TP53	Li-Fraumeni syndrome	Sarcoma, brain, adrenal cortex, leukaemia	Very early onset, often HER2-positive
PTEN	Cowden syndrome	Thyroid, endometrium, hamartomas	Variable
CDH1	Hereditary diffuse gastric cancer	Diffuse (signet-ring) gastric cancer	Invasive lobular carcinoma
PALB2, CHEK2, ATM	No single named syndrome	Pancreas (PALB2), others	Mostly ER-positive

Clinical notes

Genetic counselling and testing are offered to patients and families with suggestive histories; testing a patient's tumour can also reveal a germline mutation.
Carriers are offered intensified screening with MRI and risk-reducing mastectomy or salpingo-oophorectomy.
Founder BRCA mutations have been described in some Colombian and Hispanic populations, which makes family history especially informative.

Test yourself

Think of the answer, then tap the question to see it.

What do BRCA1 and BRCA2 normally do?

They repair DNA double-strand breaks by homologous recombination.

Which BRCA gene is linked to male breast cancer and usually ER-positive tumours?

BRCA2.

Which germline gene causes lobular breast cancer together with diffuse gastric cancer?

CDH1, which encodes E-cadherin.

Why do BRCA-deficient cancers respond to PARP inhibitors?

Blocking PARP adds a second repair defect to the homologous recombination defect, and the combined loss kills the tumour cells (synthetic lethality).

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Elsewhere in DurgiPedia

Oncogenes and tumour suppressor genes

Connections

← All of general pathology

Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: Genetics of Breast and Gynecologic Cancers (PDQ®)–Health Professional Version (National Cancer Institute, 2026); BRCA1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); BRCA2 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).

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