Genetic testing technology is extremely unreliable in detecting very rare genetic variants

According to a new study published in the BMJ journal, a technology that is extensively used by commercial genetic testing firms is “extremely unreliable” in identifying very rare variants, which means results indicating that people carry rare disease-causing genetic variants are generally wrong.

genomic sequencing

Image Credit: Gio.tto/

When researchers from the University of Exeter heard of cases where women had planned for surgeries after they were mistakenly told of having very rare genetic variations in the BRCA1 gene that could considerably raise the risk of breast cancer, they performed a large-scale study of the technology using data from almost 50,000 participants of UK Biobank.

The team discovered that the technology inaccurately detected the presence of very rare genetic variants in most of the cases.

The researchers examined SNP chips, which typically test genetic changes at hundreds-of-thousands of particular sites throughout the genome. Although the SNP chips are superior at identifying regular genetic changes that can raise the risk of various diseases, including type 2 diabetes, geneticists have known for a long time that they are less consistent at identifying rarer variation.

But this problem is less familiar beyond the genetic research community, and SNP chips are extensively employed by commercial firms that directly provide genetic testing to consumers.

SNP chips are fantastic at detecting common genetic variants, yet we have to recognise that tests that perform well in one scenario are not necessarily applicable to others. We’ve confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false-positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted.”

Caroline Wright, Study Senior Author and Professor in Genomic Medicine, University of Exeter Medical School

The researchers compared data from SNP chips with the data obtained from the more consistent tool of next-generation sequencing in a total of 49,908 UK Biobank participants, and an additional 21 individuals who shared outcomes of their consumer genetic tests through the Personal Genome Project.

The new study surmised that SNP chips performed very well when it comes to identifying common genetic variants. But rarer variation results in less reliable results. In very rare variants, found in fewer than 1 in 100,000 people, characteristic of those causing rare genetic disease, 84% were false positives in the UK Biobank participants.

In the data obtained from commercial customers, 20 of 21 people examined had at least a single false positive rare disease-causing variant that had been wrongly genotyped.

The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using a SNP chip is more likely to be wrong than right. Although some consumer genomics companies perform sequencing to validate important results before releasing them to consumers, most consumers also download their “raw” SNP chip data for secondary analysis, and this raw data still contain these incorrect results.

Dr Leigh Jackson, Study Co-Author and Lecturer in Genomic Medicine, University of Exeter

The implications of our findings are very simple: SNP chips perform poorly for detecting very rare genetic variants and the results should never be used to guide a patient’s medical care, unless they have been validated,” Dr Jackson concluded.

Journal reference:

Weedon, M. N., et al. (2021) Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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