By Kathleen Fergus, MS, CGC and Jill Simonsen

Reviewed By Beth Crawford, MS, CGC
Last Updated August 23, 2000

The link between BRCA1 and BRCA2 mutations and breast and ovarian cancer was discovered in 1994. Later, additional studies conducted with DNA samples originally donated for Tay Sachs disease research revealed that people of Ashkenazi (Eastern European) Jewish heritage are more likely to have mutations in these genes than members of the general population. Furthermore, researchers have discovered that three specific mutations in the BRCA1 and BRCA2 genes account for approximately 90 percent of the BRCA1 and BRCA2 mutations identified in Ashkenazi Jews. This is in contrast to the hundreds of unique BRCA1 and BRCA2 mutations that genetic testing has turned up in people who are not of Ashkenazi Jewish descent.

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More on Genetic Diseases in People of Ashkenazi Jewish Descent

Approximately 1 in 40 Ashkenazi Jewish individuals carries one of three BRCA1 or BRCA2 mutations, while approximately 1 in 500 members of the general population carry any BRCA1 or BRCA2 mutation.

Of the three mutations that account for the vast majority of BRCA1 and BRCA2 mutations in Ashkenazi Jews, two occur on the BRCA1 gene and one occurs on the BRCA2 gene.

• 185delAG mutation. This mutation located is on the BRCA1 gene and was the first to be linked to Ashkenazi Jews. It is found in approximately one percent of the Ashkenazi Jewish population.
• 5382insC mutation. Also located on BRCA1, this mutation is less common than the 185delAG mutation and is found in approximately 0.15 percent of individuals of Ashkenazi Jewish descent.
6174delT mutation. This mutation is located on the BRCA2 gene and is the most common of the BRCA1 and BRCA2 mutations found in the Ashkenazi Jewish population, occurring in approximately 1.5 percent of such individuals

Although these percentages may sound low, when counted together they take on more significance. Approximately 2.65 percent of the Ashkenazi Jewish population has one of these three mutations; a number far higher than the 0.2 percent of the general population that carries a BRCA1 or BRCA2 mutation.

Furthermore, the chances that a person of Ashkenazi Jewish descent has one of these mutations rises dramatically if he or she has a personal or family medical history of breast or ovarian cancer. Consider, for example, the following statistics:

• Twenty percent of Ashkenazi Jews who have been diagnosed with breast cancer before the age of 40 have a BRCA1 mutation.
• Twenty-nine percent of Ashkenazi Jews with a family history of two or more breast cancers carry one of these mutations.
• Seventy-three percent of Ashkenazi Jews with a family history that includes two or more cases of breast cancer and at least one case of ovarian cancer carry one of these mutations.

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Risk

Of course the bottom line in any discussion of cancer risk is not how many people are carriers of a specific genetic mutation, but how many of those carriers will actually develop the associated disease. In the case of Ashkenazi Jews with BRCA1 and BRCA2 mutations, a recent population-based study suggests that 56 percent of such individuals will develop breast cancer over the course of their lives, and 16 percent will develop ovarian cancer by age 70. In addition, this study showed that these two genes increase the risk of prostate cancer in men who carry mutations. Sixteen percent will develop the disease by age 70. To see how these risk statistics stack up against those of the general population, see the following table.

Why are population-based studies so powerful? Studies that start with a large and diverse population can help avoid biases that might be present, but not obvious, in studies that start with a more narrow population.

This most recent population-based study also cast great doubt on earlier studies that linked these specific BRCA1 and BRCA2 mutations to an increase in colon cancer risk. In addition, the risk estimates from the population-based study are lower than those from earlier studies that looked at cancer risk only in mutation carriers. It is not clear whether this difference is because the cancer risk is lower when an individual has these three particular mutations than if they had other BRCA1 and BRCA2 mutations, or whether the cancer risk is lower because this was a population-based study that could give more accurate risk estimates than could the earlier studies.

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Testing

Since researchers have been able to pinpoint three mutations that account for the majority of BRCA1 and BRCA2 defects in Ashkenazi Jews, genetic testing is simpler for this population than it is for the population at large. This is because DNA testing can begin with just these three mutations, making the tests less expensive and often easier to interpret than the full-sequence genetic testing that's required to identify the hundreds of BRCA1- and BRCA2-associated mutations that can arise in members of the general population. The rationale for the three mutation test is that 90 percent of the time in an Ashkenazi Jewish family, if there is a mutation it will be one of these three. If this test is negative it may be necessary to go on to the full sequence test for BRCA1 and BRCA2 to rule out a mutation as the cause for the family history.

More on Genetic Testing for Breast and Ovarian Cancer

More on Genetic Testing for Women of Ashkenazi Jewish Descent

References

BIC (2000). Breast Cancer Information Core. Website.

Couch, F. J. et al. (1997). BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 336(20): 1409-15.

Dorum, A. et al. (1999). Three per cent of Norwegian ovarian cancers are caused by BRCA1 1675delA or 1135insA. Eur J Cancer 35(5): 779-81.

FitzGerald, M. G. et al. (1996). Germ-line BRCA1 mutations in Jewish and non-Jewish women with early- onset breast cancer. N Engl J Med 334(3): 143-9.

Petrij-Bosch, A. et al. (1997). BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients [published erratum appears in Nat Genet 1997 Dec;17(4):503]. Nat Genet 17(3): 341-5.

Roa, B. B. et al. (1996). Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14(2): 185-7.

Struewing, J. P., et al. (1995). The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals [published erratum appears in Nat Genet 1996 Jan;12(1):110]. Nat Genet 11(2): 198-200.

Struewing, J. P. et al. (1997). The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336(20): 1401-8.

Szabo, C. I. and M. C. King (1997). Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60(5): 1013-20.

Thorlacius, S. et al. (1998). Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352(9137): 1337-9.

Tonin, P. w. b. o. et al. (1996). Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast Cancer Families. Nature Medicine 2: 1179-1183.