VIP Variant in BRCA1
The BRCA1 185delAG (187delAG) mutation is estimated to have arisen about 920 years ago [Article:8571953]. This mutation is one of the most common mutations identified among Ashkenazi Jewish families with a history of breast and/or ovarian cancer. The frequency of the mutation in the general Ashkenazi population, unselected for personal or family history of breast or ovarian cancer, is around 1% (see table below).
| Ashkenazi Population | Number of Individuals Tested | Number of Individuals with 185delAG* | Percent | PubMed ID |
|---|---|---|---|---|
| Israel | 369 | 3 | 0.8 | [Article:7550349] |
| Israel | 403 | 3 | 0.74 | [Article:8841191] |
| U.S./Israel | 162 | 2 | 1.2 | [Article:7550349] |
| United States | 327 | 3 | 0.9 | [Article:7550349] |
| United States | 2705 | 31 | 1.15 | [Article:8841191] |
| Australia | 1200 | 15 | 1.25 | [Article:11466700] |
| Total | 5166 | 57 | 1.1 |
*These individuals may be heterozygotic or homozygotic for the 185delAG allele.
One of the first reports of an association between the 185delAG mutation and Ashkenazim with breast or ovarian cancer was made by Shattuck-Eidens et al., in 1995 [Article:7837387]. In high-risk Ashkenazi families with a history of breast and/or ovarian cancer, the frequency of the 185delAG mutation is significantly higher than in the general Ashkenazi population. Several smaller reports indicate the mutation is present in all Ashkenazi families in their studies, or that all incidents of the mutation found were in Ashkenazim (5 of 37 families [Article:8533757], 6 of 24 families [Article:7611288], 3 of 24 families [Article:7611277]). In other studies of high-risk families with breast and/or ovarian cancer, the percentage of Ashkenazi individuals with 185delAG mutations ranged from 24% to 32% [Articles:9042929, 8651293, 9333265]. In another study, 32% of high-risk Jewish families with breast and/or ovarian cancer were found to harbor the 185delAG mutation, while this mutation was detected in 52% of the subset of families with both breast and ovarian cancer [Article:8898735].
The incidence of the 185delAG mutation in general or non-Jewish populations at high-risk for breast and/or ovarian cancer appears to be much lower than that seen for the Ashkenazi population, in the range of 1-13% [Articles:9150149, 7894492, 7837387, 7606717, 11896095].
Note that this variant is referred to in the literature as both 185delAG and 187delAG. The naming confusion is a result of the fact that the sequence from nucleotides 185-188 is 'AGAG', so that it is impossible to tell if the deletion is caused by removal of the nucleotides at positions 185-186 or at positions 187-188, as both would produce the same final sequence.
Please Note: The BRCA1 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
| Key Publications: | |
|---|---|
| Diseases | Breast Neoplasms 1 2 3 4 5 6 7 8 9 10 11 12 13 Ovarian Neoplasms 14 15 16 17 18 19 20 21 22 23 24 25 26 |
Appendix
Genomic Variant & GenBank ID: 38529572 AG > [--\] on NC_000017.9
HGVS Nomenclature: NC_000017.9:g.38529572_38529571delAG
mRNA Variant & GenBank ID: 187 AG > [--\] on U14680
Protein Variant & GenBank ID: This deletion causes a frameshift that results in premature termination of the protein at codon 39 [Article:7894492, 7894492].
GoldenPath Position: Chr17: 38529572(hg18)
DNA Source Containing Homozygous Minor Allele(Coriell Lines): White (Caucasian):
GM14090/NA14090
Key Haplotypes: See BRCA1 Haplotype Information
