Large-scale study finds genetic testing technology falsely detects very rare variants

February 15, 2021

A technology that is widely used by commercial genetic testing companies is "extremely unreliable" in detecting very rare variants, meaning results suggesting individuals carry rare disease-causing genetic variants are usually wrong, according to new research published in the BMJ.

After hearing of cases where women had surgery scheduled after wrongly being told they had very rare genetic variations in the gene BRCA1 that could significantly increase risk of breast cancer, a team at the University of Exeter conducted a large-scale analysis of the technology using data from nearly 50,000 people. They found that the technology wrongly identified the presence of very rare genetic variants in the majority of cases.

The team analysed SNP chips, which test genetic variation at hundreds-of-thousands of specific locations across the genome. While excellent at detecting common genetic variation that can increase the risk of diseases such as type 2 diabetes, geneticists have long known they are less reliable at detecting rarer variation. However, this problem is less well known outside the genetic research community, and SNP chips are widely used by commercial companies that offer genetic testing direct to consumers.

Caroline Wright, Professor in Genomic Medicine at the University of Exeter Medical School, senior author on the paper, said: "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."

The team compared data from SNP chips with data from the more reliable tool of next generation sequencing in 49,908 participants of UK Biobank, and an additional 21 people who shared results of their consumer genetic tests via the Personal Genome Project.

The study concluded that SNP chips performed extremely well in detecting common genetic variants. However, the rarer the variation was, the less reliable the results became. In very rare variants, present in fewer than 1 in 100,000 individuals, typical of those causing rare genetic disease, 84 per cent were false positives in UK Biobank. In the data from commercial customers, 20 of 21 individuals analysed had at least one false positive rare disease-causing variant that had been incorrectly genotyped.

Dr Leigh Jackson, Lecturer in Genomic Medicine at the University of Exeter and co-author of the paper, said: "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. 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."
The paper published today in the BMJ is entitled 'Using SNP chips to detect very rare pathogenic variants: retrospective population-based diagnostic evaluation'.

Notes to editors: For further context, see the joint statement from the Royal College of General Practitioners and the British Society for Genetic Medicine on direct to consumer genomic testing, which references the pre-print version of the paper.

Once the embargo lifts, the paper will publish at:

*Labels applied according to the Academy of Medical Sciences press release labelling system.

About the University of Exeter Medical School

The University of Exeter Medical School is part of the University of Exeter's College of Medicine and Health. Our mission is to improve the health of the South West and beyond, through the development of high quality graduates and world-leading research that has international impact.

As part of a Russell Group university, we combine this world-class research with very high levels of student satisfaction. Exeter has over 19,000 students and is ranked 12th in The Times and Sunday Times Good University Guide 2020.

The University of Exeter Medical School's Medicine course is in the top 10 in the Complete University Guide 2020.

The College's Medical Imaging programme is ranked in the top 5 in the Guardian Guide 2020 and the Complete University Guide 2020.

The University of Exeter entered the world top 20 for Biomedical and Health Sciences in the CWTS Leiden Ranking 2019, based on the percentage of publications ranked in the top 10 per cent most cited.

For further information:

Louise Vennells
Press and Media Manager
University of Exeter Medical School
+44 (0)1392 724927 or 07768 511866

University of Exeter

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