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

Table of Contents

STUDY AT A GLANCE

This study is about:

How a new technology could be used to help classify BRCA1 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 “variant of uncertain significance (VUS)” is a type of inconclusive genetic test result. With a VUS, 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 VUS results. Experts often use family history to help provide clues as to whether a VUS 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 VUS results of their cancer risk.

In the future, the new method described by this research could greatly improve experts ability to classify variants in BRCA1 and other genes as harmful or harmless, allowing people in VUS 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 DNA 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 DNA instructions in BRCA1 in laboratory cells. They then observed how these edited genes functioned. Almost 4,000 possible BRCA1 changes were analyzed. 

• Researchers classified changes as either harmless (no effect on normal BRCA1 function) or harmful (causing BRCA1 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 BRCA1 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 BRCA1 genetic test results. This technology applies mostly to people who received a result of a VUS.

The ability to accurately classify nearly 4,000 BRCA1 changes may prove to be a much-needed tool that researchers can use to reclassify VUS from unknown to known (harmful or harmless).

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

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Posted 9/29/18

References:

1. Findlay GM, Daza RM, Martin B, Zhang MD, Leith AP, Gasperini M, Janizek JD, Huang X, Starita LM, Shendure J. Accurate classification of BRCA1 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 DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 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

Disclosure

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.