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Study: A new method for determining whether genetic variants in BRCA1 increase cancer risk

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Table of Contents

Study at a glance In-depth review              
Study findings Limitations    
What does this mean for me?     Resources 
Questions to ask your doctor  


This study is about:

How a new technology could be used to help classify Variants of Uncertain Significance.

Why is this study important?

Genetic testing is not always straightforward. While most people who have genetic testing will test positive or negative for a gene mutation that increases cancer risk, some test results are inconclusive. A “ ()” is a type of inconclusive genetic test result. With a , experts cannot be sure that the genetic changes is harmful or harmless.

As the cost and availability of genetic testing have gone down, more people are having genetic testing, so more people are receiving results. Experts often use family history to help provide clues as to whether a result is harmful or harmless. But as genetic testing has become more widely available, more people are having testing even if they do not have a personal or family history of cancer. Finding better tools to figure out which changes are harmless and which are harmful will help genetics experts advise people with results of their cancer risk.

In the future, the new method described by this research could greatly improve experts ability to classify variants in and other genes as harmful or harmless, allowing people in families to make more informed medical decisions. But more work will be needed to validate this technology and make it more efficient and less costly before it can be used as a standard way to classify variants.

Study findings:

CRISPR-Cas9 is a simple, yet powerful technology that allows researchers to easily “gene edit” or modify the sequence of a gene. Researchers can then then see how that change affects the gene’s function. (Scientists have other gene-editing technologies, but the newer CRISPR technology is faster, easier and more effective.)

In this study, researchers used CRISP-Cas9 technology to change instructions in in laboratory cells. They then observed how these edited genes functioned. Almost 4,000 possible changes were analyzed. 

  • Researchers classified changes as either harmless (no effect on normal function) or harmful (causing not to function).
  • Researchers then compared their results to another other study that used a different approach to classify variants and also compared their results to an internationally recognized database that uses clinical information to classify changes as harmful or harmless.

The results, although not perfect, were strikingly accurate.

  • Changes that the researchers classified as harmful were generally classified as harmful in the international database
  • Nearly all changes that the researchers classified as harmless were classified as harmless in the international database.

What does this mean for me?

It’s important to understand that this technology does not impact most genetic test results. This technology applies mostly to people who received a result of a .

The ability to accurately classify nearly 4,000 changes may prove to be a much-needed tool that researchers can use to reclassify from unknown to known (harmful or harmless).

If you have had genetic testing and received a report that you have a , this technology—once it has been validated—may provide you with more information about your risk.

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Posted 9/29/18


1. Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J. Accurate classification of variants with saturation genome editing. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0461-z.

2. Starita LM, Islam MM, Banerjee T, Adamovich AI, Gullingsrud J, Fields S, Shendure J, Parvin JD. A Multiplex Homology-Directed Repair Assay Reveals the Impact of More Than 1,000 Missense Substitution Variants on Protein Function. Am J Hum Genet. 2018 Aug 24. doi: 10.1016/j.ajhg.2018.07.016.

3. Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE, Ramos EM et al. ClinGen — The Clinical Genome Resource. 2015. N Engl J Med. 372:2235-2242. DOI: 10.1056/NEJMsr1406261


FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.


This article is relevant for:

People who have a Variant of Uncertain Significance in a gene associated with cancer risk.

This article is also relevant for:

people with a genetic mutation linked to cancer risk


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Study background:

changes  are classified in three ways: as benign variants that cause no concern; as deleterious variants that can confer a high risk of cancer; and  as variants of uncertain significance or , which have an undetermined effect on cancer risk.

As of January 2018, most single base-pair changes in the gene are classified as a .  These changes are rarely seen in more than a few people. Determining whether or not these rare changes affect cancer risk is a significant challenge.  This difficulty is also reflected in the fact that hundreds of changes in have conflicting classifications between different labs.

The study authors used an innovative approach called “saturation genome editing.” Using this technology, the authors were able to make almost 4000 single-base pair changes in .  These changes were made in regions that have been shown to be important to function. When a change caused a cell to die, it was classified as harmful; in cells that lived, the change was classified as harmless. 

Researchers of this study wanted to know:

Can we develop a robust, large-scale way to classify changes in ?

Populations looked at in this study:

This research was conducted in a single human cell line (a cell line is a group of cells in a petri dish that have all descended from a single cell). However, results were compared to a database that uses clinical data to classify changes in

Study findings:  

Saturation genomic editing was applied to key regions of . Both exons (regions that code for the protein) and introns (regions  that do not code for the protein) were tested. Researchers classified nearly 4,000 changes as harmless or harmful.

Researchers compared their results from another published studys and to an internationally recognized data base that uses clinical information to classify changes in . The results, although not perfect, were strikingly accurate:

  • Almost 4,000 changes in were tested.
  • Over 400 harmful changes in exons were identified
  • Almost 300 harmful changes in introns were identified.
  • Results aligned almost perfectly with those recently reported using a complementary assay(ref #2) and with an internationally recognized dataset of clinically support variant classifications (ref #3).

Although not perfect, the results of this study are very accurate.


This study used a novel approach to classify nearly 4,000 changes in . However, the changes studied were only in a portion of the gene (changes studied were in 13 exons and surrounding introns out of the 24 exons and introns in ). This study is limited in that currently, what provides confidence to variant classification is the availability of sufficient clinical data to assign risk to a given variant. More clinical data will be needed to validate this approach. 


If validated, this approach could be a major advance over previous attempts to study the consequence of a change in in a research setting.  However, serious consideration should be given to how best to integrate this assay into reclassification of current and new never-before-seen changes in that are sure to appear. 

This research could be a very important addition to cancer genetics generally.  This approach may possibly be used to better classify changes not only in untested regions of but in other cancer predisposing genes.

Share your thoughts on this XRAYS article by taking our brief survey.

Posted 9/29/18

Questions To Ask Your Doctor
Questions To Ask Your Doctor

  • Should I see a genetics expert to help me better understand my genetic test results?
  • I have a VUS; can this new study help reclassify this change to either harmful or harmless?
  • I have a in another gene? Can this test be used to reclassify a in another gene?
  • I have a , can I participate in a research study to help scientists learn more about reclassifying variants?

Open Clinical Trials
Open Clinical Trials

The following clinical trials include genetic counseling and testing. 

Other genetic counseling or testing studies may be found here.


Updated: 02/29/2024

Find Experts
Find Experts

The following resources can help you locate a genetics expert near you or via telehealth.

Finding genetics experts

  • The National Society of Genetic Counselors website has a search tool for finding a genetic counselor by specialty and location or via telehealth. 
  • InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference. 
  • Gene-Screen is a third-party genetic counseling group that can help educate, support and order testing for patients and their families. 
  • JScreen is a national program from Emory University that provides low-cost at-home genetic counseling and testing with financial assistance available.
  • Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone. 
  • The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors. 

Related experts

Genetics clinics

Other ways to find experts

Updated: 07/21/2023

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