Identification of Medically Actionable Secondary Findings in the 1000 Genomes

Abstract

The American College of Medical Genetics and Genomics (ACMG) recommends that clinical sequencing laboratories return secondary findings in 56 genes associated with medically actionable conditions. Our goal was to apply a systematic, stringent approach consistent with clinical standards to estimate the prevalence of pathogenic variants associated with such conditions using a diverse sequencing reference sample. Candidate variants in the 56 ACMG genes were selected from Phase 1 of the 1000 Genomes dataset, which contains sequencing information on 1,092 unrelated individuals from across the world. These variants were filtered using the Human Gene Mutation Database (HGMD) Professional version and defined parameters, appraised through literature review, and examined by a clinical laboratory specialist and expert physician. Over 70,000 genetic variants were extracted from the 56 genes, and filtering identified 237 variants annotated as disease causing by HGMD Professional. Literature review and expert evaluation determined that 7 of these variants were pathogenic or likely pathogenic. Furthermore, 5 additional truncating variants not listed as disease causing in HGMD Professional were identified as likely pathogenic. These 12 secondary findings are associated with diseases that could inform medical follow-up, including cancer predisposition syndromes, cardiac conditions, and familial hypercholesterolemia. The majority of the identified medically actionable findings were in individuals from the European (5/379) and Americas (4/181) ancestry groups, with fewer findings in Asian (2/286) and African (1/246) ancestry groups. Our results suggest that medically relevant secondary findings can be identified in approximately 1% (12/1092) of individuals in a diverse reference sample. As clinical sequencing laboratories continue to implement the ACMG recommendations, our results highlight that at least a small number of potentially important secondary findings can be selected for return. Our results also confirm that understudied populations will not reap proportionate benefits of genomic medicine, highlighting the need for continued research efforts on genetic diseases in these populations.

A novel molecular diagnostics platform for somatic and germline precision oncology

“…We also detected several variants listed at the moment of clinical interpretation of results by HGMD as pathogenic (disease causing mutation or DM) but, in our view, with controversial or insufficient support in 41.67% of the cases (15/36; based on Tier‐1 genes only), which is in agreement with previous observations (Olfson et al. ; Groth et al. ).…”

Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals

“…Several previous reports have tried to overcome this issue, and one of these studies estimated the frequency of actionable variants in the diverse 1000 genomes [15]. They conducted an extensive literature survey by checking the population frequency, evidence for pathogenicity, and evaluations by expert physicians with medical specialties relevant to the conditions.…”

“…Since the ACMG released their recommendations, several groups have tried to estimate frequencies of actionable variants in 56 genes for diverse samples and by using different methods [10][11][12][13][14][15]. Using WGS or WES data, some studies [15,16] tried to estimate the frequencies of pathogenic variants in the recommended genes for European and African ancestries, and target populations of the 1000 Genomes Project.…”

“…Using WGS or WES data, some studies [15,16] tried to estimate the frequencies of pathogenic variants in the recommended genes for European and African ancestries, and target populations of the 1000 Genomes Project. Although East Asian populations were analyzed in the 1000 Genomes Project, the number of individuals for each population was not significant enough to detect rare pathogenic variants and frequency estimations.…”

Actionable Genes, Core Databases, and Locus-Specific Databases

“…These estimates are mainly based on variants already reported in HGMD Professional release followed by manual curation by specialists using PubMed and/or pathogenicity evaluation with different in silico tools that select only highly penetrant pathogenic mutations. If we restrict these different analyses to the ACMG recommended list of 56 genes, SVs have been found in a range from 1% to 5.6% of the participants (6/179 individuals [3.35%] [Xue et al., ], 19/1,000 participants [1.90%] [Dorschner et al., ], 12/1,092 participants [1.10%] [Olfson et al., ], 92/6,503 participants [1.41%] [Amendola et al., ], 623/11,068 participants [5.6%] [Gambin et al., ], 2/149 participants [2%] [Yavarna et al., ]).…”