The BRCA1 gene is cloned

Historical milestone — this page describes an event dated 1994. It is not current breaking news.

The four years between a map and a gene

In December 1990, Jeff Hall, Mary-Claire King and colleagues published a paper in Science with a plain title: linkage of early-onset familial breast cancer to chromosome 17q21.

They had not found a gene. They had found a neighborhood. Their analysis showed that in families where breast cancer struck young, susceptibility tracked with a marker on the long arm of chromosome 17. In families where breast cancer struck late, it did not.

That result told laboratories where to dig. The digging took four years.

What the 1994 paper reported

On October 7, 1994, Yoshio Miki, Jeff Swensen, Donna Shattuck-Eidens, P. Andrew Futreal, Sean Tavtigian and colleagues published their candidate in Science, volume 266, pages 66 to 71.

They used positional cloning. That means working inward from a known map location until you can read the gene itself, without knowing in advance what the gene does.

The gene they found codes for a protein 1,863 amino acids long. It was expressed in many tissues, including breast and ovary, and it looked unlike anything described before, apart from a zinc finger region near one end.

The proof was in the families. They examined eight kindreds thought to carry inherited susceptibility and found probable disease-causing mutations in five. The mutations included an 11-base-pair deletion, a single-base insertion, a stop codon, a missense substitution, and an inferred regulatory change. Different families, different errors, same gene.

BRCA2 followed a year later. Richard Wooster and colleagues reported it in Nature in December 1995. That gene had been mapped to chromosome 13.

What BRCA1 actually does

The gene turned out to be a DNA repair gene.

Cells break their own DNA constantly, and a double-strand break is the worst kind. BRCA1 and BRCA2 proteins are part of the crew that repairs those breaks accurately.

NCI explains the consequence clearly. Everyone has two copies of each gene. Inheriting one faulty copy is not enough to cause cancer, because the good copy still protects the cell. Trouble starts when that second copy is damaged during a person's life. A cell that has lost both copies cannot repair DNA properly, and it can become cancer.

That is why an inherited mutation raises risk without guaranteeing anything.

The numbers, as they stand now

NCI's current figures give a sense of scale:

• More than 60% of women who inherit a harmful BRCA1 or BRCA2 change will develop breast cancer in their lifetime. In the general population the figure is about 13%.
• About 39% to 58% of women with a harmful BRCA1 change, and 13% to 29% with a harmful BRCA2 change, will develop ovarian cancer. The general population figure is about 1.1%.
• Risks of pancreatic and prostate cancer are also raised.

These are lifetime risks for groups of people who share a genetic finding. They are not predictions about an individual, and they have been revised as larger studies have accumulated.

Who genetic counseling is for

NCI says testing should be focused on people more likely to carry a harmful change. The risk assessment usually looks at:

• A relative already known to carry a harmful BRCA1 or BRCA2 change.
• Ashkenazi Jewish heritage.
• Breast cancer at age 50 or younger, in you or in the family.
• Ovarian cancer, male breast cancer, pancreatic cancer, or metastatic or high-risk prostate cancer in you or in the family.

If any of that describes your family, the first step is a conversation with a genetic counselor rather than a mail-order test. NCI also notes that professional groups do not recommend testing children under 18, because there is nothing useful to do differently before adulthood.

Our page on genetic testing for cancer risk covers what the appointment involves. For the disease itself, see breast cancer and ovarian cancer.

What to keep in perspective

• Most breast cancer is not inherited. An inherited BRCA change explains a minority of cases.
• A positive result is a risk figure, not a diagnosis. Many carriers never develop cancer.
• A negative result in a family with no known mutation does not rule out inherited risk. Other genes exist, and some variants are still classed as uncertain.
• Credit for this discovery is genuinely shared. The 1990 mapping paper and the 1994 cloning paper came from different groups, and the race between laboratories was competitive.
• This page describes a scientific event. It is not advice about your own testing decisions.

Why it still matters

The practical legacy is not just testing. It is a whole class of drugs.

Because BRCA-mutated tumors cannot repair DNA one way, they lean on other repair routes. Blocking one of those routes with a PARP inhibitor tends to kill the tumor cell while leaving normal cells alive. Olaparib, a PARP inhibitor, was approved in the United States in December 2014, twenty years after the gene was read.

A gene identified by positional cloning, with no idea at the time what it did, eventually became a treatment target. That is the shape a lot of cancer progress takes.

Sources

• Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66-71
• Hall JM, Lee MK, Newman B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684-9
• Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995;378:789-92
• NCI: BRCA Gene Changes — Cancer Risk and Genetic Testing Fact Sheet

How this page was made

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

Cancer Explained is published by the National Cancer Information Foundation. It is not medical advice and does not suggest a test or treatment.

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