Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Amendola, Laura M.; Jarvik, Gail P.; Leo, Michael C.; McLaughlin, Heather; Akkari, Yassmine; Amaral, Michelle D.; Berg, Jonathan S.; Biswas, Sawona; Bowling, Kevin M.; Conlin, Laura K.; Cooper, Gregory M.; Dorschner, Michael O.; Dulik, Matthew C.; Ghazani, Arezou A.; Ghosh, Rajarshi; Green, Robert C.; Hart, Ragan; Horton, Carolyn; Johnston, Jennifer J.; Lebo, Matthew S.; Milosavljević, Aleksandar; Ou, Jeffrey; Pak, Christine M.; Patel, Ronak Y.; Punj, Sumit; Richards, C. Sue; Salama, Joseph; Strande, Natasha T.; Yang, Yaping; Plon, Sharon E.; Biesecker, Leslie G.; Rehm, Heidi L.

doi:10.1016/j.ajhg.2016.06.001

Cited by 228 publications

(239 citation statements)

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“…Part of the current criteria for classifying a variant is the evaluation of the observed allele frequency of the variant compared with the expected prevalence of the disease. Based on the current ACMG guidelines, the excess of individuals with a specific variant relative to the disease prevalence in the population is used as evidence that the variant may not be pathogenic (Amendola et al., ; Richards et al., ). The optimal utilization of this rule in the setting of LFS may be confounded by recent studies that have suggested a reduced cancer penetrance and broader phenotypic spectrum than previously appreciated (Amadou et al., ; Rana et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…To begin to address this issue, we assessed TP53 variants by consulting three major variant classification databases in addition to our own non‐clinical criteria. It is important to note that there are discordances even among major clinical laboratories with similar schema based on the ACMG‐AMP standard guidelines for variant classification (Amendola et al., ; Richards et al., ). Clinical or research‐based databases, such as those utilized in our analyses, have been shown to contain discordant and sometimes inaccurate interpretations of variant pathogenicity due to non‐standardized approaches (Dorschner et al., ; Shah et al., ; Yang et al., ).…”

Section: Discussionmentioning

confidence: 99%

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Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

et al. 2018

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Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 website. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555–5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400–865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype which is based upon cancer family history. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

et al. 2018

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“…Overall, many known rhodopsin phenotypes were recapitulated in yeast, a requirement for any assay of human gene function seeking to determine the clinical relevance of patient derived missense mutations (Amendola et al 2016). There are also important differences to consider when comparing our yeast-based assays to mammalian cell-based assays.…”

Section: Discussionmentioning

confidence: 99%

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

et al. 2018

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G protein-coupled receptors (GPCRs) are crucial sensors of extracellular signals in eukaryotes, with multiple GPCR mutations linked to human diseases. With the growing number of sequenced human genomes, determining the pathogenicity of a mutation is challenging, but can be aided by a direct measurement of GPCR-mediated signaling. This is particularly difficult for the visual pigment rhodopsin-a GPCR activated by light-for which hundreds of mutations have been linked to inherited degenerative retinal diseases such as retinitis pigmentosa. In this study, we successfully engineered, for the first time, activation by human rhodopsin of the yeast mating pathway, resulting in signaling via a fluorescent reporter. We combine this novel assay for rhodopsin lightdependent activation with studies of subcellular localization, and the upregulation of the unfolded protein response in response to misfolded rhodopsin protein. We use these assays to characterize a panel of rhodopsin mutations with known molecular phenotypes, finding that rhodopsin maintains a similar molecular phenotype in yeast, with some interesting differences. Furthermore, we compare our assays in yeast with clinical phenotypes from patients with novel disease-linked mutations. We demonstrate that our engineered yeast strain can be useful in rhodopsin mutant classification, and in helping to determine the molecular mechanisms underlying their pathogenicity. This approach may also be applied to better understand the clinical relevance of other human GPCR mutations, furthering the use of yeast as a tool for investigating molecular mechanisms relevant to human disease.

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“…However, a large number of variants need interpretation and subsequent classification. Classification of the clinical significance of a genetic variant ranges from benign to pathogenic and, to ensure a consistent and standardized output, variant classification must follow international consensus‐based guidelines (Amendola et al , 2016; Rehm et al , 2013; Richards et al , 2015; Matthijs et al , 2016). …”

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confidence: 99%

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

et al. 2017

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SummaryRare inherited bleeding disorders (IBD) are a common cause of bleeding tendency. To ensure a correct diagnosis, specialized laboratory analyses are necessary. This study reports the results of an upfront diagnostic strategy using targeted whole exome sequencing. In total, 156 patients with a significant bleeding assessment tool score participated in the study, of which a third had thrombocytopenia. Eighty‐seven genes specifically associated with genetic predisposition to bleeding were analysed by whole exome sequencing. Variants were classified according to the five‐tier scheme. We identified 353 germline variants. Eight patients (5%) harboured a known pathogenic variant. Of the 345 previously unknown variants, computational analyses predicted 99 to be significant. Further filtration according to the Mendelian inheritance pattern, resulted in 59 variants being predicted to be clinically significant. Moreover, 34% (20/59) were assigned as novel class 4 or 5 variants upon targeted functional testing. A class 4 or 5 variant was identified in 30% of patients with thrombocytopenia (14/47) versus 11% of patients with a normal platelet count (12/109) (P < 0·01). An IBD diagnosis has a major clinical impact. The genetic investigations detailed here extricated our patients from a diagnostic conundrum, thus demonstrating that continuous optimization of the diagnostic work‐up of IBD is of great benefit.

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Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Cited by 228 publications

References 0 publications

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

Coupling of Human Rhodopsin to a Yeast Signaling Pathway Enables Characterization of Mutations Associated with Retinal Disease

Application of whole‐exome sequencing to direct the specific functional testing and diagnosis of rare inherited bleeding disorders in patients from the Öresund Region, Scandinavia

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