PharmGKB: The Pharmacogenetics and Pharmacogenomics Knowledge Base
Search PharmGKB:?
 

Important Variant Information for BRCA1

Submitted by: Amy Hodge(PharmGKB)
Reviewed by: Under Review
Submitted date: July 17, 2006

Jump To:

There are Two Important Variants for BRCA1.

  1. BRCA1:185delAG (187delAG)
  2. BRCA1:5382insC (5385insC)


1. BRCA1:185delAG (187delAG)

Gene HGNC Name: BRCA1
Variant Summary: The 185delAG mutation is estimated to have arisen about 920 years ago [PMID: 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 7550349
Israel 403 3 0.74 8841191
U.S./Israel 162 2 1.2 7550349
United States 327 3 0.9 7550349
United States 2705 31 1.15 8841191
Australia 1200 15 1.25 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 [PMID: 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 [PMID: 8533757], 6 of 24 families [PMID: 7611288], 3 of 24 families [PMID: 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% [PMID: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 [PMID: 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% [PMID: 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.
Key PubMed IDs: PMID: 8571953, 7606717, 8533757, 7611288, 7611277, 9042929, 8651293, 9333265, 8898735, 9150149, 7894492, 7837387, 11896095, 7550349, 8841191, 11466700
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
HGVS Nomenclature: U14680:r.187_188delAG
Protein Variant & GenBank ID: This deletion causes a frameshift that results in premature termination of the protein at codon 39 [PMID: 7894492].
dbSNP rs#: na
GoldenPath Position: Chr17: 38529572 (hg18)
Key Phenotypes/Diseases: Breast Neoplasms and/or Ovarian Neoplasms  [PMID: 8571953, 7606717, 8533757, 7611288, 7611277, 9042929, 8651293, 9333265, 8898735, 9150149, 7894492, 7837387, 11896095]
DNA Source Containing
Homozygous Minor
Allele(Coriell Lines): 		White (Caucasian):
GM14090/NA14090
Key Haplotypes: See BRCA1 Haplotype Information


2. BRCA1:5382insC (5385insC)

Gene HGNC Name: BRCA1
Variant Summary: The 5382insC mutation is estimated to have arisen about 760 years ago [PMID: 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 0.25% or less (see table below).


Ashkenazi Population Number of Individuals Tested Number of Individuals with 5382insC* Percent PubMed ID
Israel 399 0 0.00 8841191
U.S./Israel 433 0 0.00 7550349
United States 2717 4 0.15 8841191
Australia 1200 3 0.25 11466700
Total 4749 7 0.15  
* These individuals may be heterozygotic or homozygotic for the 5382insC allele.

In high-risk Ashkenazi families with a history of breast and/or ovarian cancer, the frequency of the 5382insC mutation is significantly higher than in the general Ashkenazi population. In studies of high-risk families with breast and/or ovarian cancer, the percentage of Ashkenazi individuals with 5382insC mutations ranged from 6.5% to 9% [PMID: 9042929, 9333265]. In another study, 9% of high-risk Jewish families with breast and/or ovarian cancer were found to harbor the 5382insC mutation, while this mutation was detected in 16% of the subset of families with both breast and ovarian cancer [PMID:8898735].

The incidence of the 5382insC mutation in general or non-Jewish populations at high-risk for breast and/or ovarian cancer appears to be lower than that seen for the Ashkenazi population, in the range of 1-4% [PMID:9150149, 7837387, 8533757, 11896095, 7611277]. However, one report indicated 13% of high-risk families studied possessed the 5382insC mutation [PMID: 7894492 ].

Note that this variant is referred to in the literature as both 5382insC and 5385insC. The naming confusion is a result of the fact that the sequence from nucleotides 5383-5385 is 'CCC', so that it is impossible to tell at precisely which location the additional C is being inserted.
Key PubMed IDs: PMID: 8571953, 8841191, 7550349, 11466700, 9042929, 9333265, 8898735, 9150149, 7837387, 8533757, 11896095, 7611277, 7894492
Genomic Variant & GenBank ID: 38462606 C > CC on NC_000017.9
HGVS Nomenclature: NC_000017.9:g.38462606dupC
mRNA Variant & GenBank ID: 5385 C > CC on U14680
HGVS Nomenclature: U14680:r.5385dupC
Protein Variant & GenBank ID: This insertion causes a frameshift that results in premature termination of the protein at codon 1829 [PMID: 7894492].
dbSNP rs#: na
GoldenPath Position: Chr17: 38462606  (hg18)
Key Phenotypes/Diseases: Breast Neoplasms  and/or Ovarian Neoplasms  [PMID: 8571953, 9042929, 9333265, 8898735, 9150149, 7837387, 8533757, 11896095, 7611277, 7894492]
DNA Source Containing
Homozygous Minor
Allele(Coriell Lines): 		White (Caucasian):
GM13715/NA13715
Key Haplotypes: See BRCA1 Haplotype Information
The PGRN is financially supported by grants from NIGMS, NHLBI, NHGRI, NIEHS, NCI, and NLM within the NIH, HHS. PharmGKB is managed at Stanford University. This work is supported by the NIH/NIGMS Pharmacogenetics Research Network and Database (U01GM61374). ©2001-2008 PharmGKB.