EFTA01140256.pdf

Genetics itmenon College 01Medical Genetics and Genomics ACMG POLICY STATEMENT inMedicine ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing Robert C. Green, MD, MPhlu, Jonathan S. Berg, MD, PhD3, Wayne W. Grody, MD, PhD", Sarah S. Kalia, ScM, CGC', Bruce R. Korf, MD, PhD7, Christa L. Martin, PhD, FACMG8, Amy L. McGuire, JD, PhD°, Robert L. Nussbaum, MD10, Julianne M. O'Daniel, MS, CGC3, Kelly E. Ormond, MS, CGC", Heidi L. Rehm, PhD, FACMG412, Michael S. Watson, PhD, FACMGB, Marc S. Williams, MD, FACMG1d and Leslie G. Biesecker, MD's Disclaimer: These recommendations are designed primarily as an educational moult/ for medical geneticists and other health-care providers to help them provide quality medical genetic services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered indusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test. geneticists and other clinicians should apply their own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. It may be prudent, however, to document in the patient's record the rationale for any significant deviation from these recommendations. In dinical exome and genome sequencing, there is a potential for the dations, are described herein. The ACMG recommends that labora- recognition and reporting of incidental or secondary findings unre- tories performing clinical sequencing seek and report mutations of lated to the indication for ordering the sequencing but of medical the specified classes or types in the genes listed here. This evaluation value for patient care. The American College of Medical Genetics and and reporting should be performed for all clinical germline (consti- Genomics (ACMG) recently published a policy statement on clinical tutional) exome and genome sequencing, including the "normal" of sequencing that emphasized the importance of alerting the patient tumor-normal subtractive analyses in all subjects. irrespective of age to the possibility of such results in pretest patient discussions, clini- but excluding fetal samples. We recognize that there are insufficient cal testing, and reporting of results. The ACMG appointed a Work- data on penetrance and clinical utility to fully support these recom- ing Group on Incidental Findings in Clinical Exome and Genuine mendations, and we encourage the creation of an ongoing process Sequencing to make recommendations about responsible manage- for updating these recommendations at least annually as further data ment of incidental findings when patients undergo exome or genuine are collected. sequencing. This Working Group conducted a year-long consensus Genet Med advance online publication 20 June 2013 process. including an open 'bruin at the 2012 Annual Meeting and review by outside experts. and produced recommendations that have Key Words: genome; genomic medicine; incidental findings; per- been approved by the ACMG Board. Specific and detailed recom- sonalized medicine; secondary findings; sequencing; whole exome: mendations, and the background and rationale for these recommen- whole genome Exome and genome sequencing (collectively referred to in this pharmacogenomics, preconception/prenatal screening, and report as clinical sequencing) are rapidly being integrated into population screening for disease risk)" In all of these applica- the practice of medicine.12 The falling price of sequencing, tions, there is a potential for the recognition and reporting of coupled with advanced bioinformatics capabilities, is creating incidental (or secondary) findings, which are resuhs that are opportunities to use sequencing in multiple medical situa• not related to the indication for ordering the sequencing but tions, including the molecular characterization of rare diseases, that may nonetheless be of medical value or utility to the order- the individualization of treatment (particularly in cancer), ing physician and the patient Considerable literature discusses 'Division of Genetics, Department ofMedicine. Brigham and Women's Hospital and Harrold Medical School. Boston. Massachusetts, USA; :Partners Healthcare Center for Personalized Genetic Aledicine.Boston.11,12SfaCIULSCUS. USA; 'Department of Genetics. University of North Carolina at Chapel Hill School ofhledicine. Chapel HilL North Carolina, USA; 'Division hkdical Genetics. Department ofHuman Genetics. UCLA School of Medicine. Los Angeles. California USA: 'Dhision ofMolecular Pathology. Department ofPathology & Laboratory Medicine. UCLA School ofMedicine. Los Angeles. California. USA:•Dhision ofPediatric Genetics. Department of Pediatrics. UCLA School ofMedicine. Los Angeles. California USA; 'Department oiGenetics. University of Alabama. Birmingham. Alabama. USA: 'Autism and Developmental Medicine Institute. Geisinger Health System. Danville. Pennsylvania. USA: 'Center for Medical Ethics and Health Policy. Baylor College of hledicine. Houston:fens. USA: "'Division of Genomic Medicine. Department ofMedicine. and Institute (or Human Genetics. University ofCalifornia.San Francisco. San Francisco.(:311/DII113. USA; "Department of Genetics. Stanford University.Stanford. California. USA: "Department ofPathology. Brigham and Women's Hospital and Harvard Medical School. Bogen. Massachusetts. USA; nAmerican College ofMedical Genetics and Genomics. Bethesda. Maryland. USA: "Genomic Medicine Institute. Geisinger Health System. Danville. Pennsylvania. USA: "National Human Genome Research Institute. National Institutes of Health. Bethesda. Maryland. USA. Correspondence: Robert C.Green (regreenftenetics.med.harrard.edu) or Leslie U. Biesecker (leshebehelix.nih.gov) Submitted II April 2013; accepted II April 2013: advance online publication 20 lune 2013. doi:10.1038/gim.2013.73 GENETICS In MEDICINE 1 EFTA01140256 ACMG POLICY STATEMENT WIN ct a, I ACMG recommendations an incidental findings the utility and ethics of reporting incidental findings discov- DEFINITIONS ered in the course of research," but relatively little has been Clinician written about doing so in the clinical context.'" Last year, the This term refers to the individual practitioner who has direct American College of Medical Genetics and Genomics (ACMG) contact with the patient and family or a clinical team that is published a policy statement related to clinical sequencing1s responsible for direct contact with the patient and family. The that emphasized the importance of secondary or inciden- clinician should be properly trained and prepared in genetics tal results in pretest patient discussions, clinical testing, and and genomics with an understanding of genetic counseling, reporting of results. Here, we provide the recommendations of pedigree analysis, and risk assessment to provide pretest and the ACMG Working Group on Incidental Findings in Clinical posttest patient care associated with clinical sequencing." Exome and Genome Sequencing (hereafter referred to as the Working Group). These recommendations have been approved Laboratory by the Board of the ACMG. This term refers to the entity that takes responsibility for analysis, interpretation, and report generation of sequencing performed PROCESS for clinical purposes. The Working Group recognizes that in The chairs of the Working Group were appointed in November some cases, one entity may generate the raw sequencing data 2011, and a written charge to the Working Group was approved and another may further evaluate and interpret the sequence, by the ACMG Board of Directors in January 2012. The Board consider additional or confirmatory testing, and issue a clinical charged this Working Group with evaluating the need for and report. The latter is the focus of these recommendations. principles that would govern recommendations for analyzing and reporting incidental findings from sequencing in the clini- Patient cal context. The Working Group was then asked to generate an This term is used to describe adults who undergo clinical initial list of genes and categories of variants to be reported as sequencing and are competent to make their own health-care incidental findings. Working group members were appointed decisions. The term, as used here, also refers to parents of minor and approved by the ACMG Board in January 2012 and met children or guardians of decisionally impaired adults who may weekly by teleconference between January and September 2012 undergo this testing. In cases in which young children or deci- and by e-mail throughout the development of this article. The sionally impaired adults undergo sequencing, pre- and posttest Working Group began by establishing general processes for counseling and consent of parents or guardians on behalf of the accomplishing its charge. We decided to consider both broad minor or decisionally impaired adult should occur, but teen- categories of disorders as well as specific genes. The initial list of agers and mildly decisionally impaired adults should not be genes considered by the Working Group was derived from the excluded from these discussions, and assent should be sought genes evaluated in a survey of genetics experts by Green et att0 in appropriate cases. and supplemented by a provisional list of genes" being evalu- ated at the University of Washington for return of results. Primary finding The Working Group presented its principles and plans and This term is used to describe pathogenic alterations in a gene solicited feedback at an open forum at the ACMG Annual or genes that are relevant to the diagnostic indication for which Meeting in March 2012. These principles and plans were the sequencing was ordered (e.g., a mutation in MECP2 in a girl further developed based on feedback from ACMG mem- with loss of developmental milestones). bers and were provisionally reviewed by the ACMG Board in May 2012 and again in November 2012. Twenty additional Incidental finding experts were nominated by the Working Group members in This term has been used in a variety of clinical and research May 2012. Fifteen agreed to serve as external reviewers, and contexts to indicate unexpected positive findings. Other terms feedback from these additional reviewers was solicited in have been used to describe these findings, particularly when conference calls in June 2012 and by e-mail in January 2013. they are actively sought (rather than being unexpectedly dis- The recommendations and this article were revised based on covered). These terms include "serendipitous and iatrogenic" this feedback. Final approval by the ACMG Board occurred findings,16 "non-incidental secondary findings," "unantici- on 19 March 2013. pated findings:" and "off-target results." We use "incidental The Working Group used the ACMG policy statement tided findings" in this article to indicate the results of a deliberate "Points to Consider in the Clinical Application of Genomic search for pathogenic or likely pathogenic alterations in genes Sequencing"'s as a starting point for its deliberations. That doc- that are not apparently relevant to a diagnostic indication for ument includes a definition of clinical sequencing, describes the which the sequencing test was ordered. indications for such testing, and provides guidance on pretest considerations, reporting of results, genetic screening issues, WORKING GROUP CONSIDERATIONS and posttest considerations. Those issues were not revisited by The dinical utility of incidental findings this Working Group except to the extent that such consider- Some have argued that incidental findings should not be ations may be specifically affected by incidental findings. reported at all in clinical sequencing until there is strong 2 GENETICS in MEDICINE EFTA01140257 ACMG recommendations on incidental findings I GREEN et d ACMG POLICY STATEMENT evidence of benefit, whereas others have advocated that varia- findings, although we recognize that there are limited data tions in any and all disease-associated genes could be medi- available in many cases to make this assessment. cally useful and should be reported)' The Working Group Although some definitions of incidental findings allude acknowledged that there was insufficient evidence about ben- to findings that are discovered without actually searching for efits, risks, and costs of disclosing incidental findings to make results, this was not the basis for our recommendations. The evidence•based recommendations. Nonetheless, based on Working Group recommended that the laboratory actively available evidence and clinical consensus among its members, search for the specified types of mutations in the genes listed in the Working Group determined that reporting some incidental these recommendations. findings would likely have medical benefit for the patients and In making these recommendations, the Working Group families of patients undergoing clinical sequencing. In reach- addressed only the circumstance in which the report of inci- ing this consensus, we recognized that our clinical experience dental findings would be delivered to the clinician who ordered has been derived largely from patients with disease symptoms the clinical sequencing. It was expected that this clinician or positive family histories. As additional evidence accrues on would contextualize any incidental findings for the patient in the penetrance of these variants among persons without symp- light of personal and family history, physical examination, and toms or family history, these recommendations are expected other relevant findings. This places responsibility for manag- to evolve. ing incidental findings with the ordering clinician, because we The Working Group elected to present recommendations in believe that the clinician-patient interaction is the appropriate the form of a "minimum list" of incidental findings to report place for such information to be explained and discussed." from clinical sequencing. Although all the disorders are rare, most of these genes and variant categories were selected because Limitations and interpretation of incidental findings they are associated with the more common of the monogenic The Working Group recognized that when a laboratory evalu- disorders, and because the Working Group reached a consen- ates genes for the specified categories of variants recommended sus that they met criteria described below. The Working Group here as incidental findings, the analysis may not be technically specified a set of disorders, the relevant genes that are associ- equivalent to examining these genes as a primary finding. For ated with the disorders, and certain categories of variants that example, clinical sequencing could have areas of diminished or should be reported, based on a consensus•driven assessment of absent coverage in the genes examined for incidental findings clinical validity and utility. In cases in which evidence was lack- that would be filled in by Sanger sequencing or other supplemen- ing, the Working Group drew upon the clinical judgment of its tary approaches if the gene were being evaluated for a primary members. The Working Group acknowledged that its member- indication. In addition, although genome sequencing can pro- ship (and the ad hoc reviewers listed in the Acknowledgments) vide increasingly reliable information on copy-number variation were not always in complete agreement, could not fully repre- and translocations, exome sequencing is currently less reliable, sent the opinions ofothers in the field, and did not have detailed and neither technology can be used to measure tandem repeat knowledge of all the conditions that were considered. size accurately. For these reasons, we did not include some disor- The Working Group tried to include conditions on the list for ders for which structural variants (e.g., translocations and inver- which confirmatory approaches for medical diagnosis would be sions), repeat expansions, or copy-number variations are the pri- available, although we recognized that this standard could not mary cause and have not recommended that laboratories utilize be met for all the conditions listed. The Working Group pri- orthogonal techniques to search for these variants in the genes oritized disorders for which preventive measures and/or treat- named in the minimum list. Therefore, the Working Group rec- ments were available and disorders in which individuals with ommended that laboratories evaluate these genes for the speci- pathogenic mutations might be asymptomatic for long peri- fied categories of variants to the extent that the available data ods of time. In most cases, the Working Group recommended from the genome or exome sequence allow. We did not recom- restricting the variants to be reported as incidental findings to mend that laboratories ensure a depth ofcoverage for these genes those fitting two descriptive categories: "Sequence variation is equivalent to molecular testing for a primary indication. Given previously reported and is a recognized cause of the disorder" or these recommendations, the Working Group was concerned that "Sequence variation is previously unreported and is of the type a negative incidental findings report could be misconstrued by which is expected to cause the disorder").' For the purposes of clinicians or patients as an assurance of the absence of a patho- these recommendations, variants fitting these descriptions were genic variant, which is not always the case. To address this, we labeled as Known Pathogenic (KP) and Expected Pathogenic recommended that the report ofincidental findings issued by the (KP), respectively. These categories were chosen because we laboratory include distinct language differentiating the quality of recognized the challenge of attempting to report and interpret the incidental findings report from the quality ofmolecular test- variants of unknown significance as incidental findings. Given ing that would be conducted for a primary indication. the low prior probability that an individual has a monogenic On the other hand, when there is a positive incidental find- disorder that could be identified incidentally through exome or ing, the Working Group recommended that laboratories genome sequencing, we recommended that only variants with review available literature and databases at the time of the a higher likelihood of causing disease be reported as incidental sequence interpretation to ensure there is sufficient support for GENETICS in MEDICINE 3 EFTA01140258 ACMG POLICY STATEMENT GREEN eta) I ACMG recommendations en incidental findings pathogenicity before reporting a variant. The Working Group that laboratories should seek and report findings from the list recognized that there is no single database currently available described in Table 1 without reference to patient preferences. that represents an accurately curated compendium of known Autonomy is preserved since patients have the right to decline pathogenic variants, nor is there an automated algorithm to clinical sequencing if they judge the risks of possible discovery identify all novel variants meeting criteria for pathogenicity. of incidental findings to outweigh the benefits of testing. Therefore, evaluation and reporting ofpositive findings in these genes may require significant manual curation. Incidental findings in children The standards for predictive genetic testing in clinical genetics Patient preferences and incidental findings recognize a distinction between the scenario where a clinician Standards for molecular testing in clinical genetics have largely provides results to adults versus children and adolescents, with evolved around testing an affected individual or suspected car- consistent recommendations that predictive testing for adult- rier for a mutation or testing an unaffected relative of a patient onset diseases not be performed on children."-25 However, with a known mutation. In these situations, extensive pretest these recommendations can be inconsistent with the general counseling can ascertain with confidence the preference of the practice of respecting parental decision making about their individual to be tested in terms of choosing whether or not to children's health, and questions have been raised about the obtain a particular genetic test for a specific hereditary condi- sustainability of these standards in an era of comprehensive tion. By contrast, after clinical genome or exome sequencing for genomic testine One of these recent policy statements noted a specific indication, the patient has already undergone an assay "results from genetic testing of a child may have implications of all other disease•associated genes. To respect preferences in for the parents and other family members. Health-care provid- the same manner as with targeted testing, the patient whose ers have an obligation to inform parents and the child, when exome or genome is sequenced would have to undergo an exten- appropriate, about these potential implications This state- sive, and possibly overwhelming, amount of genetic counseling ment suggests an important consideration in the era ofgenomic for numerous conditions unrelated to the primary indication for medicine because after sequencing a child for a primary indica- sequencing. This will become impractical as clinical sequencing tion it becomes relatively easy for a laboratory to report a lim- becomes more common, and both its lack of standardization ited number of variants for conditions that could be medically and its application to patients of all circumstances might result important to that child's future or to the rest of the family. in deeply varying levels of truly informed preference setting. The Working Group recognized that this is a transitional Even if preferences about receiving a limited set of incidental moment in the adoption of genomic medicine where the parents findings were accurately explained, carefully noted, and clearly of children undergoing sequencing do not have easy access to communicated to the laboratory, the laboratory would have to inexpensive, readily interpretable exome or genome sequencing mask the informatics analysis of specific genes or ignore find- in order to obtain personal risk information for the conditions ings of potential medical importance in order to honor those on our minimum list In the future, when parents might all have preferences. All of this may be feasible in an environment where such access, the identification of adult•onset disease variants the laboratory is an interactive partner in the clinical assessment in their children could be restricted. But at this moment in the of a patient by clinicians skilled in genetics and genetic counsel- evolution of clinical sequencing, an incidental finding relevant ing but will become increasingly unwieldy as clinical sequenc- to adult disease that is discovered and reported to the clinician ing becomes more common and more commonly ordered by through clinical sequencing of a child may be the only way in clinicians with varying levels of ability and experience in genetic which that variant will come to light for the parent. As with the counseling. On the basis of these considerations, the Working argument against preferences, the Working Group felt that mask- Group did not favor offering the patient a preference as to ing or tailoring the reporting of such information according to whether or not their clinician should receive a positive find- the age of the patient could place an unrealistic burden on the ing from the minimum list of incidental findings described in laboratories facing increasing volumes ofclinical sequencing. The these recommendations. We recognize that this may be seen to Working Group also felt that the ethical concerns about provid- violate existing ethical norms regarding the patient's autonomy ing the clinicians ofchildren with genetic risk information about and "right not to know" genetic risk information. However, in adult-onset diseases were outweighed by the potential benefit to selecting a minimal list that is weighted toward conditions for the future health of the child and the child's parent ofdiscovering which penetrance may be high and intervention may be pos- an incidental finding for which intervention might be possible. sible, we felt that clinicians and laboratory personnel have a Therefore, the Working Group recommended that recommenda- fiduciary duty to prevent harm by warning patients and their tions for seeking and reportingincidental finding to ordering cli- families about certain incidental findings and that this princi- nicians not be limited by the age of the person being sequenced. ple supersedes concerns about autonomy, just as it does in the reporting of incidental findings elsewhere in medical practice. Circumstances not addressed in these recommendations The Working Group therefore recommended that whenever The Working Group elected not to address a number of issues clinical sequencing is ordered, the ordering clinician should dis- related to incidental findings in clinical sequencing. Conditions cuss with the patient the possibility of incidental findings and that were part of routine newborn screening were excluded 4 GENETICS in MEDICINE EFTA01140259 ACMG recommendations on incidental findings I GREEN et d ACMG POLICY STATEMENT because they have their own assessment criteria and are applied to the ordering clinician, regardless of the indication for in a specific public health framework. Similarly, these recom- which the clinical sequencing was ordered. mendations address incidental findings sought and reported e Additional genes may be analyzed for incidental vari- during clinical sequencing for a specific clinical indication but ants, as deemed appropriate by the laboratory. do not address preconception sequencing, prenatal sequenc- e Incidental variants should be reported regardless of the ing, newborn sequencing, or sequencing of healthy children age of the patient. and adults. In particular, the issues associated with genomic e Incidental variants should be reported for any clini- sequencing in healthy individuals of any age will become cal sequencing conducted on a constitutional (but not increasingly salient as costs decline and informatics interpreta- tumor) tissue. This includes the normal sample of a tion algorithms improve, but the value of population screening tumor•normal sequenced dyad and unaffected mem- for prevention and health promotion raises complex questions bers of a family trio. of potential benefits as well as downstream risks and costs that 2. The Working Group recommends that laboratories seek will need considerably more data to resolve!" We acknowl- and report only the types of variants within these genes edged but did not address the possibility that dinical sequenc- that we have delineated (Table 1). ing may be ordered by specialists who may not feel comfortable e For most genes, only variants that have been previously discussing incidental findings pertaining to another organ sys- reported and are a recognized cause of the disorder or tem, thus generating additional consultations and medical costs. variants that are previously unreported but are of the We elected not to consider questions of data ownership or the type that is expected to cause the disorder, as defined by legal ramifications of returning or withholding raw sequencing prior ACMG guidelines,* should be reported. results from families that request these. We also did not address e For some genes, predicted loss•offunction variants are issues of patents in making these recommendations or any of the not relevant (e.g., COL3A1 and most hypertrophic car- issues associated with duty to re•contact ordering clinicians and diomyopathy genes). update the interpretation of their clinical sequences.3' We have e For some genes (e.g., APOB), laboratories should only not addressed the implications of induding incidental findings report variants for certain associated conditions. in laboratory reports that will become part of the patient's health 3. It is the responsibility of the ordering clinician/team to record and the potential for discrimination that could arise from provide comprehensive pre• and posttest counseling to the this circumstance. We recognize that laboratories that adopt patient. these recommendations may add significant costs to at least e Clinicians should be familiar with the basic attributes some of their sequencing reports with primer design and Sanger and limitations of dinical sequencing. confirmation of positive findings, evidence review, report gen- e Clinicians should alert patients to the possibility that eration, and sign•out. We do not know the implications that this clinical sequencing may generate incidental findings may have on reimbursement for clinical sequencing. that could require further evaluation. There is an active debate about the return of incidental find- e Given the complexity of genomic information, the ings in genomic research, and recommendations for this set- clinical geneticist should be consulted at the appropri- ting are evolving. Although we hope that investigators find our ate time, which may include ordering, interpreting, and process and these recommendations useful in their attempts communicating genomic testing. to design thresholds and lists for the return of genomic find- 4. These recommendations reflect limitations of current ings to research participants, we did not design this list for that technology and are therefore focused on disorders that are purpose. The Working Group has designed these recommen- caused by point mutations and small insertions and dele- dations for the situation in which a clinician orders exome or tions, not those primarily caused by structural variants, genome sequencing for a specific clinical indication. In this repeat expansions, or copy-number variations. circumstance, a laboratory report will be returned to that clini- 5. The Working Group recommends that the ACMG, cian, who will ideally be in a position to integrate such findings together with content experts and other professional orga- with the medical and family history and the physical examina- nizations, refine and update this list at least annually. tion, taking into account the psychological state of the patient and the patient's family. Although we recognize that this ideal DISCUSSION may not always be realized, this is nonetheless a very different The ACMG recommends that for any evaluation of clinical scenario from the disclosure of sequence information outside sequencing results, all of the genes and types of variants in of the medical care system. The return of incidental findings Table 1 should be examined and the results reported to the discovered in the course of a clinical laboratory investigation is ordering clinician. The conditions listed in Table 1 are those consistent with such practices in other disciplines of medicine. that the Working Group and external reviewers considered most likely to be verifiable by other diagnostic methods and RECOMMENDATIONS amenable to medical intervention based on current evidence 1. Constitutional mutations found in the genes on the mini- and the clinical consensus of the Working Group members. mum list (Table 1) should be reported by the laboratory Reporting these incidental findings to the ordering clinician GENETICS In MEDICINE 5 EFTA01140260 ACMG POLICY STATEMENT GREEN ad I ACMG recommendations on incidental findings Table 1 Conditions, genes, and variants recommended for return of incidental findings in clinical sequencing PMID-Gene MIM- Reviews Typical age Variants Phenotype disorder entry of onset Gene MIM•gene Inheritance• to report° Hereditary breast and ovarian cancer 604370 20301425 Adult BRCA? 113705 AD KP and EP 612555 BRC42 600185 Li-Fraumeni syndrome 151623 20301488 Child/adult TP53 191170 AD KP and EP Peutz-leghers syndrome 175200 20301443 Child/adult STK;I 602216 AD KP and EP Lynch syndrome 120435 20301390 Adult MLH? 120436 AD KP and EP MSH2 609309 MSH6 600678 124,152 600259 Familial adenomatous polyposis 175100 20301519 Child/adult APC 611731 AD KP and EP MYH-associated polyposis; 608456 23035301 Adult MUTYH 604933 AR' KP and EP adenomas, multiple colorectal, 132600 FAPtype 2; colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas Von Hippel-Undau syndrome 193300 20301636 Child/adult VHL 608537 AD KP and EP Multiple endocrine neoplasia type 1 131100 20301710 Child/adult MEN) 613733 AD KP and EP Multiple endocrine neoplasia type 2 171400 20301434 Child/adult RET 164761 AD KP 162300 Familial medullary thyroid cancer' 1552401 20301434 Child/adult RET 164761 AD KP PTEN hamartona tumor syndrome 153480 20301661 Child/adult PTEN 601728 AD KP and EP Retinoblastoma 180200 20301625 Child RBI 614041 AD KP and EP Hereditary paraganglioma- 168000 20301715 Child/adult SOFID 602690 AD KP and EP pheochromocytoma syndrome (PGLI) 601650 SDHAF2 613019 KP (PGL2) 605373 SOFIC 602413 KP and EP (PGL3) 115310 SORB 185470 (PG14) Tuberous sclerosis complex 191100 20301399 Child TSC / 605284 AD KP and EP 613254 TSC2 191092 W77-related Wilms tumor 194070 20301471 Child WTI 607102 AD KP and EP Neurofibromatos's type 2 101100 20301380 Child/adult NF2 607379 AD KP and EP Ehlers-Danlos 130050 20301667 Child/adult COL34 I 120180 AD KP and EP syndrome, vascular type Marian syndrome, Loeys-Dietz 154700 20301510 Child/adult FBA11 134797 AD KP and EP syndromes, and familial thoracic 609192 20301312 TGFBR I 190181 aortic aneurysms and dissections 608967 20301299 610168 TGFBR2 190182 610380 SMAD3 603109 613795 611788 ACTA2 102620 MYLK 600922 MYHI 1 160745 "Someconcitians that may demonstrate semidominant inheritance (SD) have been indicated as autosomal dominant (AD) for the sake of simplicity. Others have been labeled as klinked (XL); ,KP: known pathogenic, sequence variation is previously reported and is a recognized cause of the disorder; EP: expected pathogenic, sequence variation is pre,iously unreported and is of the type that is expected to cause the disorder. Note: The recommendation to not report expected pathogenic variants for sane genes is due to the recognition that truncating variants, the primary type of expected pathogenic variants, are not an established cause of some diseases on the list. 'Although carriers may have modestly increased risk, we recommend searching only for individuals with balletic mutations; 'On the basis of evidence presented to the Waking Group after the online posting of these Recommendations, the decision was made to remove one gene, NTRK1, from the recommended list. Table 1 Continued on next page 6 GENETICS in MEDICINE EFTA01140261 ACMG recommendation on incidental findings I GREW et z4 ACMG POLICY STATEMENT Table 1 Continued PMID-Gene MIM- Reviews Typical age Variants Phenotype disorder entry of onset Gene MIM-gene Inheritance• to report" Hypertrophic cardiomyopathy, 115197 20301725 Child/adult MYBPC3 600958 AD KP and EP dilated cardiomyopathy 192600 MYH7 160760 KP 601494 613690 TNNT2 191045 KP and EP 115196 INNS 191044 KP 608751 612098 YAMS 191010 600858 MYL9 160790 301500 608758 AC7C1 102540 115200 PRKAG2 602743 GL4 300644 XL KP and EP (hemi, het, horn) 160781 AD KP LMNA 150330 KP and EP Catecholaminergic polymorphic 604772 RYR2 180902 AD KP ventricular tachycardia Arrhythmogenic right-ventricular 609040 20301310 Child/adult PKP2 602861 AD KP and EP cardiomyopathy 604400 DSP 125647 610476 607450 DSC2 125645 610193 YMEM43 612048 KP DSG2 125671 KP and EP Romano-Ward long QT syndrome 192500 20301308 Child/adult KCNCH 607542 AD KP and EP types 1, 2, and 3, Brugada 613688 KCNH2 152427 syndrome 603830 601144 SCNSA 600163 Familial hypercholesterolemia 143890 No Child/adult LOLA 606945 SD KP and EP 603776 GeneReviews APOB 107730 SD KP entry a PCSK9 607786 AD Malignant hyperthermia 145600 20301325 Child/adult RYR? 180901 AD KP susceptibility