Materials and Methods
Nominations for genes/conditions to add to or remove from the SF list were accepted from ACMG members via a nomination form (see Supplementary file S1
online) that was developed through a subcommittee of the SFWG. The form was refined based on feedback from SFWG members and clinical genetics/genomics colleagues. Data collected included phenotypes associated with the gene, ordered by prevalence, and reported variants in the gene from ClinVar and the Human Gene Mutation Database. Also collected was information required to determine whether the gene/condition warranted inclusion based on clinical features, likelihood of early clinical diagnosis by a pediatrician/internist, molecular genetic characteristics, clinical genetic testing options, and medical actionability. Initially, medical actionability was evaluated according to a semiquantitative metric that included the following major adjudication criteria: severity of disease/nature of the health threat; likelihood of the disease/health threat materializing (i.e., penetrance); efficacy of specific intervention(s); and overall strength of the current knowledge base about the gene/condition. In July 2015, a fifth criterion was added: acceptability of the proposed intervention based on its risks and benefits. The SFWG acknowledged the inherent subjectivity and difficulty of rating any given intervention as it applies to an individual but voted unanimously in favor of adding this fifth criterion. This achieved consistency with efforts of the NIH-funded Clinical Genome Resource (ClinGen)
ClinGen–the Clinical Genome Resource.
Actionability Working Group,
- Hunter J.E.
- Biesecker L.G.
- Buchanan A.
A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.
which had already applied these five criteria to assign actionability scores (called “Actionability Evidence-based Summaries”)
to genes/conditions on the SF list.
Each nomination form was completed by an ACMG member or completed by a non-member and then submitted by an ACMG member. Completed forms were reviewed by the SFWG in a study section–like model. We also reviewed the Actionability Evidence-based Summary for any genes already reviewed by the ClinGen Actionability Working Group. Each form was presented in a SFWG meeting or conference call by the submitter or a designee. After thorough discussion of the rationale for making the proposed change, SFWG members voted on whether to accept the submitter’s recommendation.
Nominations that were recommended by the SFWG were sent to the ACMG Board of Directors with a summary of the SFWG discussion, voting outcome, and a recommendation for the suggested change to the SF minimum list. The Board reviewed each recommendation on a gene-by-gene basis in July 2016 and September 2016.
The SFWG discussed and unanimously agreed on a nomenclature to support versioning of the SF list, reflecting both major and minor revisions. Major revisions could be necessary due to conceptual changes to the categories of genes/variants included or the addition or removal of many genes in a single update. A major revision will be denoted by changing the version number to the next integer (v3.0, v4.0, etc.). Minor revisions reflect addition or removal of one or a few genes or variants and will be denoted by changing the number after the decimal point (v2.1, v2.2, etc.). Any new version number will be followed by the month and year in which the update was published. The ACMG Board has approved this versioning nomenclature.
To refine the nomination form to collect all relevant information, SFWG members and colleagues were requested to complete nomination forms for 28 genes already on the SF list. Of these, the SFWG unanimously supported removal of one gene: MYLK associated with familial thoracic aortic aneurysm and dissection (FTAAD).
Between March 2015 and May 2016, five nominations for additions to the SF list were received and evaluated by the SFWG. One of these, PTCH1 associated with Gorlin syndrome/nevoid basal cell carcinoma syndrome, did not achieve SFWG consensus for addition due to insufficient evidence that knowledge of a KP/EP variant in the gene would alter medical management. Each of the other four genes—ATP7B associated with Wilson disease, BMPR1A and SMAD4 associated with juvenile polyposis, and OTC associated with ornithine transcarbamylase deficiency—received a unanimous vote from SFWG members for addition to the list. The ACMG Board subsequently reviewed and approved each of the five recommendations of the SFWG: removal of MYLK and addition of ATP7B, BMPR1A, SMAD4, and OTC.
The following paragraphs describe these genes and the rationale for removing or adding each of them according to the criteria outlined above.
Key features of MYLK
include the rarity of KP variants, all of which are loss-of-function variants, as well as the lack of an effective confirmatory test, screening modality, or intervention to prevent or reduce morbidity or mortality from FTAAD. Because aortic dissection related to variants in MYLK
often presents without a history of aortic enlargement, the intervention of echocardiogram may be falsely reassuring and may not prevent sudden cardiac death.
Mutations in myosin light chain kinase cause familial aortic dissections.
In addition, there is insufficient evidence on the appropriate age to begin medications and the efficacy of this intervention to reduce dynamic stress on the aorta.
- Milewicz D.M.
- Regalado R.E.
Thoracic Aortic Aneurysms and Aortic Dissections. GeneReviews.
The SFWG considered that additional data on MYLK
are likely to be gathered in the coming years from aneurysm genetic testing panels, and this evidence could be re-evaluated periodically for possible re-addition of MYLK
to the SF list.
is associated with autosomal-recessive Wilson disease (MIM 277900). Morbidity among homozygotes directly correlates with copper deposition in the liver, brain, and eye. The disease is progressive, and, if left untreated, premature death is likely. In some cases, liver failure may be the presenting sign. Given its long recognition as a Mendelian disorder, it is reasonable to consider Wilson disease to be at least relatively highly penetrant. Expressivity is variable. Treatment for Wilson disease involves administration of copper chelating agents and/or zinc to block intestinal absorption of copper; treatment is extremely effective when administered prior to the onset of symptoms.
Wilson Disease. GeneReviews.
- American Association for Study of Liver Diseases (AASLD)
Diagnosis and treatment of Wilson disease: an update.
- Ala A.
- Walker A.P.
- Ashkan K.
- Dooley J.S.
- Schilsky M.L.
Sanger sequencing of the ATP7B
gene is considered confirmatory in asymptomatic patients. In symptomatic patients, in addition to Sanger sequencing, the results of serum ceruloplasmin, serum copper concentration, and 14-hour urine copper excretion can be diagnostic. The ClinGen Actionability scoring process generated a high actionability score of 10/12 for copper chelation and zinc therapy in the treatment of ATP7B
-associated liver disease and/or neuropsychiatric disease.
Based on this evidence, the SFWG voted unanimously to add ATP7B
to the SF list for the recessive state in which two KP/EP variants are detected in trans
are two genes known to cause autosomal-dominant juvenile polyposis syndrome (MIM 174900), which is associated with gastrointestinal (GI) bleeding, anemia, and increased risk of colon cancer and other GI cancers. An individual with a KP/EP variant in BMPR1A
has a more than 90% chance of developing polyps and a 10–50% lifetime risk of developing cancer. The majority of patients with clinical features of the disease have colon polyps by age 20, and colon cancer typically develops by the mid-40s. Screening via endoscopy with histological confirmation of juvenile-type polyps is readily available, highly sensitive, effective at reducing morbidity, and presents minimal risk or burden. Although most individuals with a BMPR1A
variant have a positive family history, many cases remain undetected because GI cancer screening is not routine in the general population before age 50. Penetrance of KP/EP variants in SMAD4
is estimated to be approximately 20% for colon cancer by age 35 and nearly 70% by age 65, with the average age of onset reported to be in the early 40s. Gastric cancer occurs in approximately 21% of patients with gastric polyps. Screening via colonoscopy and upper GI endoscopy for polyps are effective interventions for risk reduction.
- Larsen Haidle J.
- Howe J.R.
Juvenile Polyposis Syndrome. GeneReviews.
The SFWG unanimously agreed that juvenile polyposis syndrome associated with KP/EP variants in BMPR1A
meets criteria for addition to the SF list based on the existing knowledge base.
Physicians should be aware that hereditary hemorrhagic telangiectasia syndrome is another phenotype associated with loss-of-function variants in SMAD4
. Hemorrhagic telangiectasia syndrome involves a risk of sudden death due to arteriovenous malformation rupture and aortopathy as well as morbidity due to anemia and/or hypoxia. Screening includes imaging and embolization for arteriovenous malformations.
Hereditary Hemorrhagic Telangiectasia. GeneReviews.
A patient with a KP/EP variant identified in SMAD4
is potentially at risk for juvenile polyposis and/or hemorrhagic telangiectasia syndrome and therefore should be screened for both diseases.
Ornithine transcarbamylase deficiency (MIM 311250) is a urea cycle defect caused by variants in the X-linked OTC
gene. Severely affected males present within the first week of life with hyperammonemic coma that is associated with high neonatal mortality; long-term survivors have significant neurologic deficits and intellectual disability.
The clinical, biochemical, and molecular spectrum of ornithine transcarbamylase deficiency.
Penetrance in hemizygous males is nearly 100%, although cases in which there is partial expression of the mutated allele with residual enzyme activity often present later with milder symptoms. In heterozygous females, penetrance estimates range from approximately 20 to 30%.
- Batshaw M.L.
- Msall M.
- Beaudet A.L.
- Trojak J.
Risk of serious illness in heterozygotes for ornithine transcarbamylase deficiency.
- Gyato K.
- Wray J.
- Huang Z.J.
- Yudkoff M.
- Batshaw M.L.
Metabolic and neuropsychological phenotype in women heterozygous for ornithine transcarbamylase deficiency.
The phenotype among affected females varies widely from mild to severe, depending primarily on the pattern of X-inactivation of the gene in hepatocytes.
The clinical, biochemical, and molecular spectrum of ornithine transcarbamylase deficiency.
Interventions exist to prevent crises and ameliorate outcomes, including protein restriction in the diet and medications that remove ammonia by alternate metabolic pathways.
- Batshaw M.L.
- MacArthur R.B.
- Tuchman M.
Alternative pathway therapy for urea cycle disorders: twenty years later.
These treatments are most useful in symptomatic heterozygous females and among males with later onset or partial disease. Medical management may also include the potential for prolonged hospitalization during illness as well as dialysis for acute crises with hyperammonemia to help prevent or minimize brain damage. For males with severe disease who present in the neonatal period, and for some males and females with later-onset disease, liver transplantation is recommended due to the high risk for recurrent hyperammonemia, subsequent neurological deterioration, and/or death.
- Lichter-Konecki U.
- Caldovic L.
- Morizono H.
Ornithine Transcarbamylase Deficiency. GeneReviews.
OTC deficiency is included on newborn screening panels in only some states; however, males with severe disease often become ill in the first 2–3 days of life, when newborn screening results are not yet available. Given the morbidity and mortality risks, the SFWG voted unanimously to add ornithine transcarbamylase deficiency associated with KP/EP variants in the OTC
gene to the SF list.
In selecting the variant types to recommend for return, the SFWG considered using the terminology of “pathogenic” and “likely pathogenic” according to updated variant classification criteria
- ACMG Laboratory Quality Assurance Committee
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
published since the original policy statement, but ultimately decided to maintain the terminology of KP and EP. This decision was based on a recognition that classifying a variant as likely pathogenic is more burdensome for laboratories, whereas an EP classification is simpler because it is limited to loss-of-function variants and novel missense variants need not be analyzed as SFs.
depicts the “ACMG SF v2.0 (September, 2016)” updated list of SFs recommended for return from clinical GS. Table 2
summarizes the updates to the SF list.
Table 1ACMG SF v2.0 genes and associated phenotypes recommended for return of secondary findings in clinical sequencing
Table 2Four genes added and one gene removed from the ACMG secondary findings minimum list
This article highlights the process for nominating changes to the ACMG Secondary Findings minimum list. This process and form were piloted by SFWG members and colleagues before soliciting nominations from the ACMG membership. Goals for the nomination process were to (i) make the nomination form accessible through the ACMG website; (ii) collect information from the broader community to inform decision-making by the SFWG and the Board; and (iii) update the gene list at least annually in a way that is inclusive of ACMG members. We hope to transition to a web-based nomination process such that submission of supporting information would directly populate a database.
The nomination form has been designed to accept nominations for additions to as well as removals from the SF list. Five formal nominations for adding genes/conditions to the SF list were received between March 2015 and March 2016, and four of these have been added to the ACMG SF v2.0 list based on unanimous consensus among SFWG members and approval by the ACMG Board. In addition, one gene has been recommended and approved for removal. It is our hope that this article will stimulate additional nominations from the ACMG membership and broader medical community for genes to consider adding to the ACMG SF v2.0 list, as well as further assessment of the evidence to support genes/conditions already on the list.
Our group has attempted to uphold the principles outlined in the original policy statement
- American College of Medical Genetics and Genomics
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
while expanding on certain aspects. We have continued to focus primarily on SFs related to monogenic disorders for which there is evidence of clinical utility. Additionally, we have attempted to standardize the evaluation of current and prospective genes by adopting a process that includes a semiquantitative metric for determining actionability that is consistent with the goals of the ClinGen Actionability Working Group. We continue to support the reporting of known or expected pathogenic variants, but we do not recommend reporting variants of uncertain significance as SFs. Among the challenges inherent in developing and curating this list, we recognize the presumption of high penetrance for these genes and diseases based on potentially biased case ascertainment. Specifically, literature reports for many of these conditions represent assessment of disease probands and their families. Over time, we may discover that penetrance for some of these conditions is lower than current estimates suggest. We anticipate that the increasing availability of large population databases, such as the Exome Aggregation Consortium (ExAC), will be helpful in refining estimates of penetrance, which may inform future curation of the ACMG SF v2.0 list.
We acknowledge the contributions of the original ACMG Incidental Findings Working Group for their groundbreaking efforts to begin the important process of identifying and reporting actionable genetic variants based on genome-scale sequencing, including those who are not members of the current SFWG: Robert C. Green, Jonathan S. Berg, Wayne W. Grody, Amy L. McGuire, Julianne M. O’Daniel, Heidi L. Rehm, Marc S. Williams, and Leslie G. Biesecker. We thank former members of the Secondary Findings Maintenance Working Group for their insights and feedback, specifically Robert Nussbaum, Will Parsons, and Richard Sharp. We are also grateful to cardiogenetics counselors at GeneDx who completed nomination forms for genes on the SF list to pilot this process; Kyle Retterer, manager of Exome BioInformatics at GeneDx, who provided exome data related to PGx variants; Michelle Carillo at CPIC, who prepared PGx summaries for SFWG review; and Katrina Goddard and the ClinGen Actionability Working Group for sharing their approach and evaluations of certain genes.
The Board of Directors of the American College of Medical Genetics and Genomics approved this statement on 26 September 2016.
Received in revised form:
© 2017, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics