Most valuable, medically actionable genes for reporting

Recently the American College of Medical Genetics and Genomics (ACMG) published the newest updated guide for doctors reporting secondary findings after a patient’s clinical exome or genome sequencing. This was a particularly exciting update due to the increase in number of medically relevant genes, now totaling 73 genes! And apparently from now on these will be updated annually (each January)! These guidelines were originally released in 2013 with v.2.0 released in 2016, but the enormous uptake of DNA testing in medicine now apparently allows for far more frequent analysis. This is truly fantastic news for this still a growing field of medicine.

This list of genes is extremely valuable for any doctor dealing with medical genomics as it consists of genes not only vetted for their association to a condition, but these are also genes where a medical actionability is available to the doctors. In this context, actionability refers to available medical intervention as defined by current standards of care.

The ACMG list of genes alone is worth the price of medical DNA testing because it is information provided on a golden platter to potentially help those with identified mutations. Because of the potential value to the patient, these are medically actionable genes that should always be evaluated as part of clinical DNA testing even if the genes are unrelated to the original indication for testing. Hence the reference to such results as secondary or incidental findings.

The number of genes on this list does not mean that the number of medically actionable genes are this small. The list of all medically actionable genes is much larger (and growing). The ACMG list is restricted on purpose due to their use for reporting as secondary findings. For example: genes involved in disorders that are typically diagnosed clinically (not requiring the need of DNA testing) are not included; genes in disorders where timing of the diagnosis is not critical for treatment efficacy; genes of disorders that might be too complicated to determine with a high accuracy by using certain genomic technologies (such as copy number variations where a same gene can be copied, increasing its count from expected number); or genetic disorders where a lifestyle change is the primary beneficial intervention (and we all know that lifestyle quality is the best way to fight your negative health outcomes – so watch your diet, exercise, don’t smoke and get a good sleep!).

Rather, the selected genes are known to result in a high chance of indicating the presence of a clinical risk if pathogenic mutations are found. This is referred to as disease penetrance, and genetic mutations (more appropriately referred to as variants) that are highly likely to result in a clinical outcome are referred to as high penetrance conditions. There can always be additional mitigating factors leading to reduced penetrance and these always must be taken into account when deciding on patient management. Overall, the higher the disease penetrance of a given mutation, the higher the positive predictive value of such a genetic mutation (the likelihood that the test correctly predicts the clinical outcome, or a true measure of the value of any medical test but rarely if ever discussed, probably because that value is usually quite low for any test). Finally, the included genetic disorders are expected to exhibit high morbidity and/or mortality, or include disorders where earlier detection reduces long-term mortality. Thus, the final outcome is “a minimum list of genes that places a limited excess burden on patients and clinical laboratories while maximizing the potential to reduce morbidity and mortality”. These are categorized into four groups: genes involved in hereditary cancer (comprising the second largest group with 28 genes); genes of inborn errors of metabolism (4 genes), cardiovascular (largest group with 33 genes), and all other conditions (labelled miscellaneous with 8 genes).

In this post we break these down for easy access. We also add some of the available interventions for the listed conditions to indicate the potential value of foreknowledge, although these are for illustration purposes and are not exhaustive and subject to change. For simplicity, the mode of inheritance is removed (whether the genetic disorder is inherited in autosomal dominant or autosomal recessive fashion, with only one condition on the list being inherited through sex X chromosome). OMIM stands for Online Mendelian Inheritance in Man which is a comprehensive database of all identified human genes with their corresponding resulting traits, including diseases. OMIM reference numbers are included with links directly to the database for further background information.

ACMG v3.0 gene list

P in the above table refers to pathogenic variants while LP refers to likely pathogenic variants, both of which are expected to be reported to doctors when genomics tests are undertaken. What is the difference between the two? Pathogenic variants have established evidence of their contribution to a resulting disease. Likely pathogenic variants on the other hand are expected to meet 90% confidence threshold for pathogenicity based on the underlying evidence. Historical evidence demonstrates that likely pathogenic variants are rarely downgraded in their threat status, thus currently the benefits of reporting such a variant that could point to important interventions for a patient outweighs the risk of a variant being incorrectly identified (a false positive).

In the accompanying 2021 ACMG general policy statement for reporting medical genomics secondary findings, it is reported that secondary findings are observed somewhere between 1—6% of the time, with actionable secondary findings observed 2—3% of the time. These are based on thousands of participants, and thus provide a realistic threshold of frequency. This also shows you the value of the ACMG gene list that is curated to be most impactful as it consists of a majority of the possible typical findings in a population. Considering that interventions for these genetic conditions are available, this is good news for those undergoing possible medical DNA testing in that if some pathogenic mutation is uncovered, it very well might fall in the actionable category. However, there are literally thousands of other possibilities, most of which are very rare in occurrence.

Thus, if you have already undertaken a genomic test and did not obtain any pathogenic or likely pathogenic results, consider yourself that lucky one in about 95%. Of course, Merogenomics always recommends eventual re-interpretation of your DNA sequence to capture the latest medical advances in this field. But most of the current ACMG genes have been known for a while, so you can rest assured that with high quality DNA test you indeed likely do not have any serious condition to be addressed.

If you have not investigated your full genome, or are a clinic interested in incorporating medical DNA testing, Merogenomics is here for you to get you prepared.

This article has been produced by Merogenomics Inc. and edited by Jason Chouinard, B.Sc. Reproduction and reuse of any portion of this content requires Merogenomics Inc. permission and source acknowledgment. It is your responsibility to obtain additional permissions from the third party owners that might be cited by Merogenomics Inc. Merogenomics Inc. disclaims any responsibility for any use you make of content owned by third parties without their permission.

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