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What was the purpose of the original ACMG recommendations?
The American College of Medical Genetics (ACMG) published a statement in 2013 on “secondary findings”, which are DNA results unrelated to the clinical issue that prompted testing in the first place.
For example, when a child has developmental problems, whole exome or whole genome sequencing may be ordered. The parents are sequenced, too, in order to help interpret the child’s sequence. Given the parents’ sequences are available, the question arises whether there is a need to inform the parents of findings that could impact their own health.
The 2013 statement identified 56 medically-actionable genes. A lab can offer to report the findings in these genes to healthy patients who give consent. The recommendation was considered voluntary. In 2017, the list was revised to 59 genes and is often called the “ACMG59”.
How are the ACMG recommendations being used today?
Labs are using the recommendations for their original purpose, and there is another way they are being used, too. Given that these 59 genes have been listed as having enough evidence to support medical management when findings are present, some labs started offering them to healthy adults interested in genetic screening. The idea was, if these could be reported in healthy adults pursuing sequencing for unrelated clinical indications, then other healthy adults might want to know, too.
Are there limitations to using the ACMG recommendations in healthy adults?
The ACMG made a statement in April 2019 that the recommendations were not intended for screening purposes. These genes have not been studied extensively in healthy populations. We don’t know whether a finding in one of these genes in a healthy family has the same clinical meaning as the families where the genes were originally studied. There may be other genetic factors, perhaps unknown at this time, that influence whether the family members express the gene.
Clinical studies of population screening have initiated through US-based institutions like the National Institutes of Health, Geisinger, Mayo Clinic, and Intermountain Health and by nations like South Korea, India, France, the United Kingdom, Singapore, and Australia. These ongoing studies may begin to shed light on how to interpret results in healthy populations.
1. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–574.
2. Kalia SS, Adelman K, Bale SJ, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–255.
3. Karow, J. Illumina Says Population Sequencing, DTC Will Continue to Grow in the Long Term. GenomeWeb. July 30, 2019. Accessed July 30, 2019 at https://www.genomeweb.com/sequencing/illumina-says-population-sequencing-dtc-will-continue-grow-long-term
4. ACMG Board of Directors. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019; Published Online April 29.