Keeping Up With ACMG: Adding genes to secondary findings list for clinical sequencing

Last month, the American College of Medical Genetics and Genomics (ACMG) updated their guidelines for reporting secondary findings in clinical exome and genome sequencing. These guidelines contain a set of genes that can harbor variants, or mutations, that are a) potentially harmful and b) medically actionable. In short, anyone who receives clinical exome or genome sequencing, for whatever reason, may also want to learn whether they have a potentially harmful mutation on this list of genes — knowing this information could even save their life.

ACMG came out with its first list of secondary findings in 2013, which included 56 genes (and noted their associated conditions). In 2017, they updated to 59 genes. Most conditions are associated either with cancer risk, or with cardiovascular health. All conditions are ones that doctors can help patients manage or prevent.

According to Fulgent’s own internal data, along with a handful of available research studies, 3–5% of people on average will test positive for a variant in one of these genes — or roughly one out of every 25 individuals.

Now, for the first time since 2017, ACMG has released new guidelines in response to new information from medical literature and the genetics community. When evaluating potential additions to their list of secondary findings, the working group considered actionability (can something be done about these results once they’re known?), severity (how serious are the symptoms?), penetrance (how many individuals with this mutation actually have symptoms?), and other clinical evidence.

“Our group worked very hard on this update, taking a thoughtful and careful approach that balances the goals of keeping it as a minimum list while also providing results that will impact patients and their families in a positive way,” said lead author of the new guidelines and co-chair of the ACMG Secondary Findings Working Group, David T. Miller.

The result is 14 new genes on the list: some of the newly-added genes are associated with conditions already on the list, like hereditary breast cancer and cardiomyopathy; whereas some are associated with newly-appearing conditions like biotinidase deficiency and maturity onset diabetes of the young (MODY).

Perhaps the most remarkable piece of information to come out of the recent updates is the fact that, moving forward, ACMG intends to make updates to their secondary findings list annually (a big change from once every four years). As a lab committed to flexibility and better patient outcomes, we’ll continue to stay on top of these changes.