ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing

Abstract

In clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing, which emphasized the importance of disclosing the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. We recommend that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the ‘normal’ of tumor-normal subtractive analyses in all subjects, irrespective of age, but excluding fetal samples. We recognize that there are insufficient data on clinical utility to fully support these recommendations and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies

“…The latter model contained variants inherited from either parent that were (1) listed in the Human Gene Mutation Database (HGMD) or internally classified as pathogenic or likely pathogenic; (2) loss of function variants such as nonsense, frameshifts, and canonical splice sites; and (3) found in genes that cause imprinted disorders. The patient and both parents were provided with a complementary analysis of secondary findings in the minimum list of genes recommended by the American College of Medical Genetics and Genomics 11. There were no reportable secondary findings in anyone.…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…In these circumstances, patients should indicate if they wish to be informed of incidental findings. These findings represent significant genetic variants in a specific group of genes (unrelated to PPGLs) that are implicated in disorders that require medical action, such as those specified in recommendations by the American College of Medical Genetics and Genomics (ACMG) 29 .…”

“…When a blood sample is not available, laboratories can accept buccal cells either as a cheek swab or in saliva obtained with specific collection kits containing preservatives 30 . DNA extraction and quality assessment should follow standard procedures established for conventional genetic testing 29,31,32 .…”

“…Alternatively, formalin-fixed paraffin embedded (FFPE) sections or other fixed tumour material (for example, maintained in alcohol) might also be acceptable; however, the quality of DNA from these materials is variable and can be suboptimal 33,34 . DNA from the tumour should be processed and assessed for quality according to standard protocols 29,31,32 . Over the past few years, protocols for DNA, and even RNA, isolation from FFPE samples have considerably improved, and technical adaptations for handling potential artefacts generated from these materials have yielded increasingly reliable sequencing data, which has expanded the use of FFPE in clinical settings 35 .…”

How Far Do We Go With Genetic Evaluation? Gene, Panel, and Tumor Testing

“…The American College of Medical Genetics and Genomics published a policy statement on clinical sequencing that included exome and genome sequencing. 47 The policy statement recommended that constitutional mutations from a panel of 56 disease-associated genes be reported to the ordering clinician, regardless of the indication for which the clinical sequencing was ordered (Table 5). These genes were chosen because they result in disorders for which preventive strategies and/or treatments are available.…”