Study Estimates Ashkenazi Jewish Women’s Risk of Having Mutations Other Than BRCA1 and BRCA2

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About 5% to 10% of breast cancers are thought to be hereditary, caused by mutated genes passed from parent to child.

Genes are short segments of DNA (deoxyribonucleic acid) found in chromosomes. DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.

Think of your genes as an instruction manual for cell growth and function. Abnormalities in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. A genetic error that causes harm is called a mutation.

Many inherited breast cancer cases are associated with two gene mutations: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).

The average woman in the United States has about a 1 in 8, or about 12%, risk of developing breast cancer in her lifetime. Women who have a BRCA1 or BRCA2 mutation (or both) can have up to an 80% risk of being diagnosed with breast cancer during their lifetimes. Breast cancers associated with an abnormal BRCA1 or BRCA2 gene tend to develop in younger women and occur more often in both breasts than cancers in women without these abnormal genes.

Women with a BRCA1 or BRCA2 gene mutation also have an increased risk of developing ovarian, colon, and pancreatic cancers, as well as melanoma.

You are substantially more likely to have a genetic mutation linked to breast cancer if:

  • You have blood relatives (grandmothers, mother, sisters, aunts) on either your mother's or father's side of the family who had breast cancer diagnosed before age 50.
  • There is both breast and ovarian cancer on the same side of the family or in a single individual.
  • You have a relative(s) with triple-negative breast cancer.
  • There are other cancers in your family in addition to breast, such as prostate, melanoma, pancreatic, stomach, uterine, thyroid, colon, and/or sarcoma.
  • Women in your family have had cancer in both breasts.
  • You are of Ashkenazi Jewish (Eastern European) heritage.
  • You are African American and have been diagnosed with breast cancer at age 35 or younger.
  • A man in your family has had breast cancer.
  • There is a known abnormal breast cancer gene in your family.

Ashkenazi Jewish women have a much higher risk of having one of three founder mutations in the BRCA1 and BRCA2 genes. This is part of the reason why Ashkenazi Jewish women have a much higher-than-average risk of breast cancer.

A founder mutation is a specific gene mutation in a population that was founded by a small group of ancestors that were geographically or culturally isolated. Because the population was isolated, the rate of founder mutations in descendants is much higher than it would be if the population were larger and comingling with more genetically diverse people.

Still, there are some Ashkenazi Jewish women who have been diagnosed with breast cancer who test negative for one of the BRCA1 or BRCA2 founder mutations. Researchers wondered if offering Ashkenazi Jewish women comprehensive genetic testing for all mutations linked to breast cancer would be beneficial.

A study suggests that offering comprehensive genetic testing for all mutations linked to breast cancer to Ashkenazi Jewish women, rather than simply testing for only the three BRCA1 or BRCA2 founder mutations, would help prevent breast cancer in this high-risk population.

The study was published online on July 20, 2017 by the journal JAMA Oncology. Read “Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women.”

Mary-Claire King, professor of medical genetics at the University of Washington, is one of the authors of the study. Dr. King is the scientist who discovered that mutated BRCA1 and BRCA2 were linked to a higher risk of breast cancer.

To do the study, the researchers did genetic testing on blood samples from 1,007 women in the New York Breast Cancer study. The blood samples were tested for all known genetic mutations linked to breast cancer.

The New York Breast Cancer Study was started in 1996 to identify all the genes responsible for a higher risk of breast cancer among Ashkenazi Jewish women. Between 1996 and 2000, women who experienced a first diagnosis of breast cancer and who identified themselves and all four grandparents as Ashkenazi Jewish were invited to participate. The women were treated at 12 major cancer centers in the New York City metropolitan area and continue to be followed.

The genetic testing results showed that:

  • 903 women (89.7%) did not have one of the three BRCA1 or BRCA2 founder mutations
  • 104 women (10.3%) had a BRCA1 or BRCA2 founder mutation

Of the 903 women without a BRCA1 or BRCA2 founder mutation:

  • 7 women (0.8%) had a different mutation in the BRCA1 or BRCA2 gene
  • 31 women (3.4%) had a mutation in another gene linked to breast cancer

Only four of the seven women with a different BRCA1 or BRCA2 mutation had a family history that suggested that they might have a higher than average risk of breast cancer.

Of the 31 women with a mutation in a gene other than BRCA1 or BRCA2:

  • 29 women had a mutation in the CHEK2 gene
  • 1 woman had a mutation in the BRIP1 gene
  • 1 woman had a mutation in the NBN gene

Of the 29 CHEK2 mutations:

  • 24 were CHEK2 p.S428F mutations, which have been previously identified as an Ashkenazi Jewish founder mutation that increases breast cancer risk 2 to 3 times higher than average
  • 4 were CHEK2 c.1100delC, which appears widely in Europe
  • 1 was CHEK2 c.444(+1)G>A, which also appears widely in Europe

Overall, about half the women with a genetic mutation linked to breast cancer had no close family history of breast or ovarian cancer:

  • Of the 111 women with a BRCA1 or BRCA2 mutation, 57 (51.4%) had a mother or sister that had been diagnosed with breast or ovarian cancer and 54 (48.6%) did not.
  • Of the 31 women with a mutation in the CHEK2, BRIP1, or NBN gene, 14 (45.2%) had a mother or sister diagnosed with breast or ovarian cancer and 17 (54.8%) did not.

According to this study, an Ashkenazi Jewish woman who has been diagnosed with breast cancer who doesn’t have a founder BRCA1 or BRCA2 mutation has about a 1% risk of having a different BRCA1 or BRCA2 mutation. If the woman was diagnosed before age 40, this risk increases to about 3%. The risk that an Ashkenazi Jewish woman who has been diagnosed with breast cancer who doesn’t have a founder BRCA1 or BRCA2 mutation has a CHEK2 or other mutation linked to breast cancer is about 3% to 4%.

“Among [New York Breast Cancer Study] participants, approximately half of the patients with a damaging mutation in any breast cancer gene did not have a family history suggesting inherited predisposition,” the researchers wrote. “Mutations in these families were likely inherited from fathers, and the combination of small family size and chance in genetic transmission yielded few female relatives carrying mutant alleles. Therefore, to limit genetic testing to patients with a suggestive family history is to miss about 50% of patients with actionable mutations. The most recent national screening guidelines recommend genetic testing for all Ashkenazi Jewish patients with breast cancer. This recommendation is fine, but testing women only after they develop cancer severely limits the power of precision medicine. To discover a mutation only after cancer is diagnosed is a missed opportunity to have prevented that cancer.”

If you are an Ashkenazi Jewish woman, you may want to talk to your doctor about this study and ask if having a comprehensive genetic test for all genetic mutations linked to breast cancer makes sense for you and your unique situation.

For more information on genetic and breast cancer risk, visit the Genetics page in the Breastcancer.org Lower Your Risk section.


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