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ACMG Updates Gene List for Labs Reporting Clinical Sequencing Secondary Findings

NEW YORK — The American College of Medical Genetics and Genomics has updated its list of genes for which it recommends laboratories report findings. It now includes 73 genes.

The ACMG first recommended in 2013 that labs conducting clinical genome or exome sequencing report secondary findings for a set of 56 genes. This list encompassed genes in which variants predisposed people to conditions like hereditary cancer syndromes and were medically actionable. An update to the list in 2016 added four more genes but removed one.

As it reported today in Genetics in Medicine, an ACMG working group has now added 14 more genes to its list of genes for which secondary results should be reported. In an accompanying policy update, the working group further noted its plans to update this list — now dubbed ACMG SF v3.0 — yearly.

"We hope to engage the community more to contribute to this process and get a regular schedule for laboratories to anticipate any release of an updated list," Christa Lese Martin, the director of the Autism and Developmental Medicine Institute at Geisinger Health System and co-chair of the ACMG Secondary Findings Working Group, said in an email. "We're learning about new gene-disease relationships and new treatments at a rapid pace and we want to keep up with those that have the potential to be the most medically actionable."

For this update, the working group members reviewed not only genes newly recommended by ACMG members and external groups for inclusion, but also ones considered previously that did not make the list and ones other organizations have deemed actionable. Four subgroups — one focusing on genes linked to hereditary cancer, inborn errors of metabolism, and cardiovascular conditions and one miscellaneous group — reviewed the candidates, which were then voted on by the full working group and further evaluated by the ACMG board of directors.

The new additions to the gene list include PALB2, which is tied to hereditary breast and/or ovarian cancer; TTN and FLNC, which are associated with dilated cardiomyopathy; and GAA, which is related to Pompe disease.

"There are a number of factors that we take into careful consideration when deciding whether to include a gene-disease pair on the ACMG secondary findings list," David Miller, a medical geneticist at Boston Children's Hospital and co-chair of the ACMG Secondary Findings Working Group, said in an email. "These considerations include, but are not limited to, ability to detect genetic risk variants through standard exome or genome sequencing, severity of the condition and degree of risk conferred by variants in the gene, and actionability of the information."

In its policy statement, the working group emphasizes the need for the gene list to balance the benefit to patients with the burden on laboratories and clinicians to review and report these results.

The group noted that it considered the inclusion of pharmacogenomic genes and variants — the RYR1 gene has been included since ACMG SF v1.0 — but concluded that that key pharmacogenomic variants or haplotypes cannot easily be determined through exome sequencing. Some, for instance, are located in promoter or introns, while others are copy-number variants.

The working group further plans to make updates to the list annually, and is targeting January for its yearly releases, but may make other updates if urgent changes are needed. To that end, it encourages ACMG members and other professional societies to nominate genes for inclusion on the list as well as alert the organization to any new data about any gene on the list that could affect patient care.

Meanwhile, it expects its policy statement to be updated less often, about every three to four years.