Journal article
Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group
Genetics in medicine, Vol.26(3), p.101036
03/2024
DOI: 10.1016/j.gim.2023.101036
PMCID: PMC10939896
PMID: 38054408
Abstract
Genetic variants at the low end of the penetrance spectrum have historically been challenging to interpret because their high population frequencies exceed the disease prevalence of the associated condition, leading to a lack of clear segregation between the variant and disease. There is currently substantial variation in the classification of these variants, and no formal classification framework has been widely adopted. The Clinical Genome Resource Low Penetrance/Risk Allele Working Group was formed to address these challenges and promote harmonization within the clinical community.
The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.
We formally recognize risk alleles and low-penetrance variants as distinct variant classes from those causing highly penetrant disease that require special considerations regarding their clinical classification and reporting. First, we provide a preferred terminology for these variants. Second, we focus on risk alleles and detail considerations for reviewing relevant studies and present a framework for the classification these variants. Finally, we discuss considerations for clinical reporting of risk alleles.
These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.
Details
- Title: Subtitle
- Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group
- Creators
- Ryan J Schmidt - Children's Hospital of Los AngelesMarcie Steeves - Color (United States)Pinar Bayrak-Toydemir - University of UtahKatherine A Benson - Royal College of Surgeons in IrelandBradley P Coe - BC Children's HospitalLaura K Conlin - University of PennsylvaniaMythily Ganapathi - Columbia University Irving Medical CenterJohn Garcia - Invitae (United States)Michael H Gollob - Toronto General HospitalVaidehi Jobanputra - Columbia University Irving Medical CenterMinjie Luo - Children's Hospital of PhiladelphiaDeqiong Ma - Yale UniversityGlenn Maston - Quest Diagnostics (United States)Kelly McGoldrick - Ambry Genetics (United States)T Blake Palculict - GeneDx, Gaithersburg, MDTina Pesaran - Ambry Genetics (United States)Toni I Pollin - University of Maryland, BaltimoreEmily Qian - Yale UniversityHeidi L Rehm - Broad InstituteErin R Riggs - Autism & Developmental Medicine InstituteSamantha L P Schilit - Woman's HospitalPanagiotis I Sergouniotis - University of ManchesterTatiana Tvrdik - Emory UniversityNicholas Watkins - Sinai Health SystemLauren Zec - Natera (United States)Wenying Zhang - Cincinnati Children's Hospital Medical CenterMatthew S Lebo - Woman's HospitalClinGen Low Penetrance/Risk Allele Working GroupNifang Niu - Stead Family Department of Pediatrics
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.26(3), p.101036
- DOI
- 10.1016/j.gim.2023.101036
- PMID
- 38054408
- PMCID
- PMC10939896
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- U24 HG009649 / NHGRI NIH HHS U24 HG006834 / NHGRI NIH HHS U24 HG009650 / NHGRI NIH HHS U41 HG006834 / NHGRI NIH HHS
- Language
- English
- Date published
- 03/2024
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701653502771
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