ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Luo, Xi; Feurstein, Simone; Mohan, Shruthi; Porter, Christopher C.; Jackson, Sarah; Keel, Siobán; Chicka, Michael C.; Brown, Anna L.; Kesserwan, Chimene; Agarwal, Anupriya; Luo, Minjie; Li, Zejuan; Ross, Justyne; Baliakas, Panagiotis; Pineda-Álvarez, Daniel E.; DiNardo, Courtney D.; Bertuch, Alison A.; Mehta, Nikita; Vulliamy, Tom; Wang, Ying; Nichols, Kim E.; Malcovati, Luca; Walsh, Michael F.; Rawlings, Lesley; McWeeney, Shannon K.; Soulier, Jean; Raimbault, Anna; Routbort, Mark J.; Zhang, Liying; Ryan, Gabriella; Speck, Nancy A.; Plon, Sharon E.; Wu, David; Godley, Lucy A.

doi:10.1182/bloodadvances.2019000644

Cited by 124 publications

(116 citation statements)

References 98 publications

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“…For the dominant gene in the hereditary cancer panel, the pathogenic probability of the homozygous variant is very low, which supports the assignment of BP2 criteria. In addition, a similar refinement of BP2 criteria has also been specified to individual genes of interest by ClinGen Expert Panel Groups, including CDH1 (Lee et al, 2018) and RUNX1 (Luo et al, 2019). For some unidentified variants, due to a lack of necessary supporting data, the refinement of BP2 criteria can make the clinical significance clearer and to some extent reduce the proportion of unidentified variants.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer SIGVAR expanded 28 criteria to 48 criteria by combining the most recent guidelines, which were adapted based on considerations of gene specificity, disease specificity and level of evidence strength Gelb et al, 2018;Karczewski et al, 2019;Lee et al, 2018;Luo et al, 2019;Mester et al, 2018;Oza et al, 2018). A detailed description of these 48 criteria is shown in Figure 1.…”

Section: Criteria Assignment and Scoring Systemmentioning

confidence: 99%

“…With the rapid development of next-generation sequencing (NGS) technologies, the use of genetic test results to guide clinical diagnosis and medication has received increasing attention (Biesecker & Green, 2014). However, with hundreds to thousands of variants per individual across genome sequencing, accurately interpreting the clinical significance of variants and their relationship with clinical symptoms is a key component of accurate diagnosis that has a serious impact on clinical care (Luo et al, 2019). To standardize the interpretation of variants, the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG-AMP) published a joint consensus recommendation that provided a set of criteria and specific terms to interpret and describe the clinical significance of variants in Mendelian disease (Richards et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…To further promote the consistency of interpretation, the Clinical Genomic Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group has provided more detailed guidance and recommendations on the application of some criteria in the ACMG-AMP guidelines, including the use of PVS1 , the level of evidence strength of some criteria (e.g., PP1, PS2/PM6, PS4, PM4, etc.) (Luo et al, 2019), setting the allele frequency (AF) threshold (BA1, BS1, PM2) (Gelb et al, 2018;Oza et al, 2018), etc. In addition, the SVI Working Groups have successively published optimized guidelines for specific diseases (such as hearing loss (Oza et al, 2018), RASopathy phenotype (Gelb et al, 2018), etc.…”

Section: Introductionmentioning

confidence: 99%

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Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

Liu

Wang

et al. 2020

Preprint

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The American College of Medical Genetics and Genomics and the Association for Molecular Pathology published guidelines in 2015 for the clinical interpretation of Mendelian disorder sequence variants based on 28 criteria. ClinGen Sequence Variant Interpretation (SVI) Working Groups have developed many adaptations or refinements of these guidelines to improve the consistency of interpretation. We combined the most recent adaptations to expand the criteria from 28 to 48 and developed a tool called Cancer SIGVAR to help healthcare workers and genetic counselors interpret the clinical significance of cancer germline variants, which is critical for the clinical diagnosis and treatment of hereditary cancer. Our tool can accept VCF files as input and realize fully automated interpretation based on 21 criteria and semi-automated interpretation based on 48 criteria. We validated our tool on the ClinVar and CLINVITAE benchmark databases for the accuracy of fully automated interpretation, achieving an average consistency for pathogenic and benign assessment up to 93.40% and 82.54%, respectively. We compared Cancer SIGVAR with a similar tool, InterVar, and analyzed the main differences in criteria and implementation. In addition, to verify the performance of semi-automated interpretation based on 48 criteria, we selected 911 variants from two benchmark databases and reached an average classification consistency of 98.35%. Our findings highlight the need to optimize automated interpretation tools based on constantly updated guidelines.

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Section: Discussionmentioning

confidence: 99%

Section: Criteria Assignment and Scoring Systemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

Liu

Wang

et al. 2020

Preprint

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“…Reflecting the importance of a collaborative approach to germline variant curation in haematological disease, the Myeloid Malignancy Variant Curation Expert Panel was established in 2018. The first guidance document, specifically on curation of RUNX1 variants, was published in 2019 21 with dedicated documents on other genes highlighted in the WHO classification expected to follow. Expansion of the WHO classification in the next iteration is also likely, with the recent description of other genotype–phenotype associations, including EFL1 and DNAJC21 (implicated in SDS like disease), SAMD9 (MIRAGE syndrome), SAM9DL (ataxia pancytopenia syndrome) and MECOM 22‐24 .…”

Section: Inherited Bone Marrow Failure Syndromes and Inherited Predismentioning

confidence: 99%

Diagnostic evaluation and considerations in hypocellular bone marrow failure—A focus on genomics

Fox

Wood

Ritchie

et al. 2020

Int J Lab Hematology

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Hypocellular bone marrow failure (BMF) has myriad differential diagnoses, most simply considered as acquired and inherited disorders, which are frequently indistinguishable upon morphologic examination of the blood and bone marrow. Accurate diagnosis is critical to optimization of management and begins with a detailed history (including family history) and physical examination. Next‐generation sequencing technologies complement traditional testing techniques (such as chromosomal fragility and telomere length assessment) and have a broad application in the diagnosis and prognostication of BMF, with the importance of detection of both germline changes and also somatic variants increasingly well understood and appreciated. There is increasing awareness of germline predisposition to haematological malignancy, which incorporates but is not limited to the traditional inherited BMF syndromes and which raises challenges for counselling, monitoring and treatment of people who harbour a germline lesion. There are many benefits to both patients and their kindred of accurate determination of the precise germline change underlying heritable bone marrow diseases, along with its associated mode of inheritance. While individually, these diseases are rare, collectively they are not so and there are many collaborative efforts underway to document the natural history of these disorders, the associated phenotypes and the ever‐increasing list of variants which have sufficient evidence to warrant the ascription of a pathogenic classification. We describe the many diagnostic considerations when evaluating newly presenting patients with hypocellular BMF, with a focus on genomic assessment, which is relevant in both germline and acquired diseases.

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Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes

et al. 2021

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Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventytwo (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia -11, congenital neutropenia-5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

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ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Abstract: Key Points The ClinGen MM-VCEP has specified RUNX1-specific curation rules to address gene function, gene-specific domains, and phenotypic criteria. RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the need for expert variant curation.

Cited by 124 publications

References 98 publications

Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

Cancer SIGVAR: A semi-automated interpretation tool for germline variants of hereditary cancer-related genes

Diagnostic evaluation and considerations in hypocellular bone marrow failure—A focus on genomics

Spectrum of hematological malignancies, clonal evolution and outcomes in 144 Mayo Clinic patients with germline predisposition syndromes

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