Welcome to the BRCA Exchange, where you can search BRCA1 and BRCA2 variants in our expertly curated and maintained data portal. This site allows you to access important, up-to-date information about a BRCA variant, such as its clinical significance. To begin, notice the search bar on the home page. This search bar accesses our databases directly, and can handle any identifying names for the variant or variants you are searching for. Here are some examples of what can be typed in this search box:

• BRCA1 or BRCA2 (Gene Symbol)
• BRCA1 c.1105G>A (Gene + HGVS Nucleotide)
• c.1105G>A (HGVS Nucleotide)
• chr17:g.4305831 (Genomic Nomenclature)
• IVS19-1179G>T, 2043G>C (BIC Designation)
• NM_007924.3 (Transcript Identifier)
• p.(Pro1238Leu) (HGVS Protein)
• P1238L (Abbreviated Amino Acid Change)

Clicking the magnifying glass will execute a search for the variants that fit your search criteria. To learn more about HGVS nomenclature, visit the HGVS Nomenclature portion of the Reference Guide (found below). A table of all matching variants is provided once you have used the search box. You can sort search results alphabetically by clicking any column header once. The list will be alphabetized based on the column you clicked. Clicking once more will sort search results in reverse-alphabetical order. When you have identified your variant of interest in the list, you can click anywhere in the variant’s data row to access the Variant Detail Page. The Variant Detail Page provides an organized summary of the searched variant’s information, including its aliases, its clinical significance, the date it was last evaluated, and other relevant data. Information is grouped into tiles for your convenience.

Please note that searching for a variant using a genomic coordinate will return all variants that match according to any of the hg38, hg19, or hg18 genome builds. For example, if you search for a variant using its hg38 coordinate, and it happens to match the coordinate of some variant in the hg19 build, both variants will be returned in the search. In this case, make sure to verify that the coordinate(s) and genome build are correct once you navigate to the Variant Details Page.

A variant that is Not Yet Reviewed is simply a variant that has not yet been interpreted by the ENIGMA consortium. Accordingly, the variant will be marked as “Not Yet Reviewed” in the ENIGMA Classification tile on the Variant Details Page. A “Not Yet Reviewed” variant is not the same as a Variant of Uncertain Significance (VUS). Such a variant might still have ClinVar or LOVD interpretations available. These interpretations, from sources other than ENIGMA, will be found in the Detail View, alongside other helpful information such as Allele Frequencies.

Genetic tests use a specific naming system to indicate which variation a patient has. These results appear as strings of letters and numbers that are listed as a variant. Some examples include:

• BRCA1 or BRCA2 (Gene Symbol)
• BRCA1 c.1105G>A (Gene + HGVS Nucleotide)
• c.1105G>A (HGVS Nucleotide)
• chr17:g.4305831 (Genomic Nomenclature)
• p.(Pro1238Leu) (HGVS Protein)

A variant may sometimes be called a mutation, in particular if there is evidence to indicate that it is pathogenic or likely pathogenic. Variant is a more general term, and will be used in this guide. Variant names, particularly those in HGVS format, adhere to consistent and systematic patterns. These patterns utilize numbers, letters, and abbreviations to indicate 3 basic things:

1. Which coordinate system is being used?
2. Where does a variant occur within the gene?
3. What is unique at this location?

Every variant has multiple names, depending on the type of name. As an analogy, consider that UC Santa Cruz is located at 1156 High St. Santa Cruz, CA. The GPS coordinate for this address are 40.741895N,-73.989308W. Much like the same place can be named with both an address and a GPS coordinate, one variant can actually have multiple names. Names differ because of the various coordinate systems that are used for variant naming.

For more information on variant naming, please visit our more extensive resotrce on Further Demystifying Variant Naming

There are two main reasons you might not find a variant you searched. The first is that the variant you searched originates from a privately operated testing company that has not yet shared the variant with a public database. A second reason your search might have failed is that you misspelled the variant in the search query. Variant names are cryptic, so try double checking to make sure you entered it correctly. As a reminder, a variety of nomenclature standards can be searched in our search box:

• BRCA1 or BRCA2 (Gene Symbol)
• BRCA1 c.1105G>A (Gene + HGVS Nucleotide)
• c.1105G>A (HGVS Nucleotide)
• chr17:g.43058314 (Genomic Nomenclature)
• IVS19-1179G>T, 2043G>C (BIC Designation)
• NM_007924.3 (Transcript Identifier)
• p.(Pro1238Leu) (HGVS Protein)
• P1238L (Abbreviated Amino Acid Change)

If you would like to check whether the company who did your genetic test contributes variants to BRCA Exchange, contact us at brca-exchange-contact@genomicsandhealth.org.

The Variant Details page is displayed once you have chosen a single variant from a set of search results. This page is a “bird’s eye view” of the variant in question, based on publicly available data. This page will tell you all the standard aliases of the variant, its most definitive classification, and a brief history of variant interpretations. These details originate from large databases, rather than individual submissions from people who have undergone BRCA testing.

Variant Details in the Summary ViewCopy URL

The Summary View contains an abridged view of the variant data in BRCA Exchange, including a definitive, expertly reviewed ENIGMA interpretation. For all publicly available data on a variant, click the "Show Detail View for this Variant" button at the bottom of the Variant Details Page.

Variant Names TileCopy URL

• GeneCopy URL

  The name of the gene on which the variant was found, as named by the HGNC. This will be either BRCA1 or BRCA2.

• HGVS NomenclatureCopy URL

  A nomenclature system standardized by the Human Genome Variation Society (HGVS) which utilizes coordinates to name variants across genomic DNA, coding DNA, RNA, and protein molecules.

  Each coordinate provides an indicator of the biomolecule being referred to ('c.', 'g.', 'p.'), a location in that biomolecule ('12345'), and an indication of what changed in the variant ('G>A', 'insA', 'dupT', 'del15', 'Asp...Asn'). Most variant aliases utilize this standard nomenclature:

  • HGVS NucleotideCopy URL

    HGVS variant alias which references the nucleotide change based on the location in the coding DNA, not the genomic DNA.

  • HGVS RNACopy URL

    The variant alias that uses RNA location.

  • HGVS ProteinCopy URL

    The predicted protein-level change (if any) that would be introduced by the genomic variant.

  • Genomic Nomenclature GRCh38Copy URL

    HGVS variant alias which references the nucleotide in genomic DNA, per the GRCh38 genome build. Click alias to access the UCSC Genome Browser.

  • Genomic Nomenclature GRCh37Copy URL

    HGVS variant alias which references the nucleotide in genomic DNA, per the GRCh37 genome build. Click alias to access the UCSC Genome Browser.
  • For more information on HGVS nomenclature, visit the HGVS site.

• Transcript IdentifierCopy URL

  These identifiers, which typically start in ‘NM’, are gene-specific, not variant-specific. They are generally used to keep track of different transcripts submitted to databases such as RefSeq, and are carried over to ClinVar. BRCA Exchange mainly uses two transcript identifiers. There is one main transcript used for BRCA1 (NM 007294.3) and another identifier used for BRCA2 (NM 000059.3). Other, less common transcripts are also present in the database.

• Abbreviated AA ChangeCopy URL

  A shortened abbreviation of the HGVS Protein alias using one-letter abbreviation for amino acids.

• BIC designationCopy URL

  A variant alias presented in BIC Nomenclature, which predates HGVS nomenclature and thus follows a different format.

Clinical Significance TileCopy URL

This tile organizes ENIGMA classifications and contextual information for the variant.

• ENIGMA interpretationCopy URL

  The most definitive, expertly reviewed interpretation for the variant according to ENIGMA criteria.

• IARC ClassCopy URL

  Clinical Classification provided by the International Agency for Research on Cancer.

• The rest of the fields in this this tile contain various citations, evidence, and other sources related to ENIGMA’s assessments

Previous Versions TileCopy URL

Here you will find a list of release dates and the interpretation as of that date. Clicking on the date takes you to the release notes, which provide you with summaries of changes, as well as a link to download the entire BRCA Exchange output as of that release date. This feature can be used to look at original variant interpretations alongside the data that informed them. These sets can be thought of as ‘variant time capsules,’ containing the data that was available when that release took place.

BRCA Exchange is updated through monthly data releases. These releases utilize an automated pipeline that retrieve the most recent information available from source databases, which include 1000 Genomes, BIC, ClinVar, ESP, gnomAD, ExAC, ExUV, LOVD, and ENIGMA. Release Notes are available for each data release. The release notes are available for each release date, and include data summaries on new variants, removed variants, new classifications, and known issues. The software used for each release is open source, and available at https://github.com/BRCAChallenge/brca-exchange/commit/8d436ee6a7b13831b7bbd5bf4e7426abe52aa923

The BRCA Exchange is a curated data platform that provides information on variants of specific genes: BRCA1 and BRCA2. Rather than contributing new information about a variant, the BRCA Exchange becomes a single source that collects and organizes existing information. The BRCA Exchange retrieves data from a variety of databases, such as ClinVar and LOVD. Using these sources, BRCA Exchange answers three basic questions about a variant:

• What is the most definitive clinical interpretation available for this variant?

• When was this interpretation made?

• What publicly available data informed this interpretation?

There are two data views used by BRCA Exchange to aid researchers and clinicians who work with BRCA1 and BRCA2. The Summary View of BRCA Exchange will only display variant aliases, ENIGMA variant interpretations, and a brief interpretation history. The ENIGMA Consortium assesses variant pathogenicity using an expertly developed set of BRCA1 and BRCA2 classification criteria. The Detail View contains all publicly available data on a variant. Thus, this view of the data provides a more complete, but also more complicated, characterization of a variant. Using multiple large-scale sources and two different views, BRCA Exchange serves as a contextualized resource for curation of BRCA variant data.

Rather than obtaining data through single-submitters, BRCA Exchange aggregates large scale data from database contributors, and is currently limited to the BRCA1 and BRCA2 genes. Accordingly, public databases such as ClinVar and LOVD are sources for the BRCA Exchange. Other sources include public population reference sets such as ExAC, and pre-compiled sources of information relevant to BRCA1 and BRCA2 variant classification.

Aggregation consolidates different kinds of data on the same variant, thus enriching BRCA1 and BRCA2 variant interpretations. Instead of searching through multiple databases separately, trying to piece together a variant's significance, a user can view most of the available BRCA data in one place. Additionally, other public databases collect general genome-wide variant data on many diverse disease genes, whereas the BRCA Exchange streamlines the sharing of specific types of data for the well-known BRCA1 and BRCA2 genes. For example, we use ExAC datasets that have TCGA data removed. BRCA Exchange also includes bioinformatic predictions and other variant annotations useful for variant classification. These specific data types help facilitate better variant interpretation.

Importantly, two different data views are available on BRCA Exchange: the Summary View and the Detail View. In order to provide unambiguous interpretations, the Summary View displays abridged variant data. In this view, only interpretations from the ENIGMA Expert Review panel are presented, providing a more simple view of trustworthy information. However, more complete data is still available through the Detail View. The comprehensive data provided in this second view includes classic genomic statistics, such as allele frequencies, as well as data unique to BRCA1 and BRCA2, such as bioinformatic predictions of variant effect, and prior probability of pathogenicity based on bioinformatic and curated knowledge of clinically important protein functional domains. The data compiled supports variant classification using qualitative criteria, and also using the quantitative multifactorial likelihood analysis approach. This detailed data aids variant interpretation, and can be better utilized in a gene-specific data environment such as BRCA Exchange.

Ultimately, BRCA Exchange aggregates BRCA1 and BRCA2 data in one place, with the intention of streamlining interpretation for these genes’ variants.

ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) is an international consortium of researchers who provide expert opinions on the clinical significance of variation in BRCA1, BRCA2, and other breast cancer genes. This consortium serves as the BRCA expert review body of ClinGen. ENIGMA uses classification criteria tuned specifically for the BRCA genes to evaluate the clinical significance of BRCA1/2 variants. Evidence reviewed includes many different types of data, including population frequencies, clinical information, and epidemiological measures. This data also includes effects of variation on transcript and protein structure and function. All available information is combined to estimate the probability that a variant is cancer-causing, using qualitative (rules-based) criteria and/or the quantitative (statistical) multi-factorial likelihood analysis method.

To learn more about ENIGMA, visit their website or read this paper.

To learn more about ENIGMA’s classification criteria, access detailed descriptions here.

Patient-Facing WebsitesCopy URL

• National Cancer Institute
• Facing Our Risk of Cancer Empowered

General Information on BRCA and Genetic TestingCopy URL

• BRCA Mutations: Cancer Risk and Genetics Testing (National Cancer Institute)
• FORCE: National Comprehensive Cancer (NCCN) Guidelines
• FORCE: Genetic testing for hereditary breast and ovarian cancer
• FORCE: Benefits and limitations of genetic testing

Finding Doctors and Genetic CounselorsCopy URL

• National Society of Genetic Counselors: Find a Genetic Counselor
• Brave Bosom: How Do I Find a Good Doctor?

Genetic Test ResultsCopy URL

• FORCE: Types of Test Results
• FORCE: Positive Test Results
• FORCE: Variants of Uncertain Significance
• FORCE: Uninformative Tests
• FORCE: Negative Test Results

Data Sharing Information & Initiatives:Copy URL

• ClinGen: Learn How You Can Share Your Data
• Brave Bosom Blog: Data Sharing from a Patient’s Perspective