. 2024 Mar;26(3):101036.

doi: 10.1016/j.gim.2023.101036. Epub 2023 Dec 3.

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group

Ryan J Schmidt¹, Marcie Steeves², Pinar Bayrak-Toydemir³, Katherine A Benson⁴, Bradley P Coe⁵, Laura K Conlin⁶, Mythily Ganapathi⁷, John Garcia⁸, Michael H Gollob⁹, Vaidehi Jobanputra¹⁰, Minjie Luo⁶, Deqiong Ma¹¹, Glenn Maston¹², Kelly McGoldrick¹³, T Blake Palculict¹⁴, Tina Pesaran¹³, Toni I Pollin¹⁵, Emily Qian¹⁶, Heidi L Rehm¹⁷, Erin R Riggs¹⁸, Samantha L P Schilit¹⁹, Panagiotis I Sergouniotis²⁰, Tatiana Tvrdik²¹, Nicholas Watkins²², Lauren Zec²³, Wenying Zhang²⁴, Matthew S Lebo²⁵; ClinGen Low Penetrance/Risk Allele Working Group

Collaborators, Affiliations

Collaborators

ClinGen Low Penetrance/Risk Allele Working Group:
Alicia Byrne, Amanda Spurdle, Blake Palculict, Bradley Coe, Ma Deqiong, Elaine Lyon, Emily Groopman, Emily Qian, Erik Puffenberger, Erin Riggs, Fergus Couch, Glenn Maston, Hannah Dziadzio, James Harraway, Jessica Mester, John Garcia, Jordan Lerner-Ellis, Katherine Benson, Kayleigh Avello, Kelly McGoldrick, Laura Conlin, Lauren Zec, Marcie Steeves, Marcy Richardson, Matt Lebo, Melissa Kelly, Michael Gollob, Minjie Luo, Mythily Ganapathi, Nicholas Watkins, Nifang Niu, Panagiotis Sergouniotis, Pinar Bayrak-Toydemir, Ryan Schmidt, Samantha Schilit, Sarah Richards, Tina Pesaran, Toni Pollin, Vaidehi Jobanputra, Wenying Zhang, Wuyan Chen, Yuxin Fan

Affiliations

¹ Children's Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA. Electronic address: rschmidt@chla.usc.edu.
² Color Health, Burlingame, CA.
³ Department of Pathology, University of Utah Molecular Genetics and Genomics, ARUP Laboratories, Salt Lake City, UT.
⁴ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Ireland.
⁵ Department of Pathology & Lab Medicine, BC Children's & BC Women's Hospitals, Vancouver, Canada.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA.
⁷ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
⁸ Invitae, San Francisco, CA.
⁹ Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Toronto General Hospital and Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁰ New York Genome Center, New York, NY; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
¹¹ DNA diagnostic lab, Department of Genetics, School of Medicine, Yale University, New Haven, CT.
¹² Quest Diagnostics, Inc., Hillsboro, OR.
¹³ Ambry Genetics, Aliso Viejo, CA.
¹⁴ GeneDx, Gaithersburg, MD.
¹⁵ University of Maryland School of Medicine, Baltimore, MD.
¹⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT.
¹⁷ Center for Genomics Medicine, Massachusetts General Hospital, Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
¹⁸ Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA.
¹⁹ Mass General Brigham, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA.
²⁰ Division of Evolution, Infection and Genomics, University of Manchester, Manchester, United Kingdom.
²¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
²² Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Canada.
²³ Natera, Inc., Austin, TX.
²⁴ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
²⁵ Mass General Brigham, Brigham and Woman's Hospital, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: mlebo@bwh.harvard.edu.

PMID: 38054408
PMCID: PMC10939896
DOI: 10.1016/j.gim.2023.101036

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group

Ryan J Schmidt et al. Genet Med. 2024 Mar.

. 2024 Mar;26(3):101036.

doi: 10.1016/j.gim.2023.101036. Epub 2023 Dec 3.

Authors

Collaborators

ClinGen Low Penetrance/Risk Allele Working Group:
Alicia Byrne, Amanda Spurdle, Blake Palculict, Bradley Coe, Ma Deqiong, Elaine Lyon, Emily Groopman, Emily Qian, Erik Puffenberger, Erin Riggs, Fergus Couch, Glenn Maston, Hannah Dziadzio, James Harraway, Jessica Mester, John Garcia, Jordan Lerner-Ellis, Katherine Benson, Kayleigh Avello, Kelly McGoldrick, Laura Conlin, Lauren Zec, Marcie Steeves, Marcy Richardson, Matt Lebo, Melissa Kelly, Michael Gollob, Minjie Luo, Mythily Ganapathi, Nicholas Watkins, Nifang Niu, Panagiotis Sergouniotis, Pinar Bayrak-Toydemir, Ryan Schmidt, Samantha Schilit, Sarah Richards, Tina Pesaran, Toni Pollin, Vaidehi Jobanputra, Wenying Zhang, Wuyan Chen, Yuxin Fan

Affiliations

¹ Children's Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA. Electronic address: rschmidt@chla.usc.edu.
² Color Health, Burlingame, CA.
³ Department of Pathology, University of Utah Molecular Genetics and Genomics, ARUP Laboratories, Salt Lake City, UT.
⁴ School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Ireland.
⁵ Department of Pathology & Lab Medicine, BC Children's & BC Women's Hospitals, Vancouver, Canada.
⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA.
⁷ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
⁸ Invitae, San Francisco, CA.
⁹ Inherited Arrhythmia and Cardiomyopathy Program, Division of Cardiology, Toronto General Hospital and Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
¹⁰ New York Genome Center, New York, NY; Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY.
¹¹ DNA diagnostic lab, Department of Genetics, School of Medicine, Yale University, New Haven, CT.
¹² Quest Diagnostics, Inc., Hillsboro, OR.
¹³ Ambry Genetics, Aliso Viejo, CA.
¹⁴ GeneDx, Gaithersburg, MD.
¹⁵ University of Maryland School of Medicine, Baltimore, MD.
¹⁶ Department of Genetics, Yale University School of Medicine, New Haven, CT.
¹⁷ Center for Genomics Medicine, Massachusetts General Hospital, Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
¹⁸ Geisinger Autism & Developmental Medicine Institute, Lewisburg, PA.
¹⁹ Mass General Brigham, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA.
²⁰ Division of Evolution, Infection and Genomics, University of Manchester, Manchester, United Kingdom.
²¹ Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
²² Department of Pathology and Laboratory Medicine, Sinai Health System, Toronto, Ontario, Canada Department of Molecular Genetics, University of Toronto, Toronto, Canada.
²³ Natera, Inc., Austin, TX.
²⁴ Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
²⁵ Mass General Brigham, Brigham and Woman's Hospital, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, MA. Electronic address: mlebo@bwh.harvard.edu.

PMID: 38054408
PMCID: PMC10939896
DOI: 10.1016/j.gim.2023.101036

Abstract

Purpose: 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.

Methods: The work presented here is the product of internal and community Likert-scaled surveys in combination with expert consensus within the Working Group.

Results: 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.

Conclusion: These recommendations support harmonized interpretation, classification, and reporting of variants at the low end of the penetrance spectrum.

Keywords: Association studies; Clinical disease risk assessment; Penetrance; Risk allele; Variant classification.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Figures

**Figure 1.. Harmonization of Terminology and Classification Across the Penetrance Spectrum.**
Risk alleles, low penetrance variants, and high penetrance variants are separated by their associated penetrance (e.g. absolute risk of disease associated with the variant). No definitive quantitative boundaries have yet been determined to separate these variant classes. These classes of variants can also be differentiated by their primary type of genetic evidence and therefore require different classification frameworks. Note that a framework for low penetrance variants has not yet been established. Classification tiers across these frameworks can be harmonized by equivalent confidence based on the supporting evidence. *This publication ^#,

See this image and copyright information in PMC

References

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Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group

Collaborators

Affiliations

Recommendations for risk allele evidence curation, classification, and reporting from the ClinGen Low Penetrance/Risk Allele Working Group

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources