Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

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Criteria Specification

ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Description : MM-VCEP ACMG/AMP specifications for RUNX1

Version : 2.0.0 Release Notes :

(1) New REVEL thresholds for PP3 ≥ 0.88 and for BP4 ≤ 0.50 (originally PP3 ≥ 0.75 and BP4 ≤ 0.15). (2) Use SpliceAI as the primary in-silico splicing predictor replacing MES and SSF. The thresholds for SpliceAI ≥ 0.38 for PP3 and ≤ 0.20 for BP4. (3) PP3 can be applied for missense, synonymous, intronic and non-coding variants if the variant impacts splicing, including the creation of cryptic novel splice sites. (4) New conservation threshold for phyloP100 way (GRCh38/hg38) ≤2.0 for BP7 (originally PhyloP score < 0.1). (5) New amino acid range for PM1_supporting and PM4_supporting to AA 89-204 (originally AA105-204). (6) Apply PM5_supporting to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4). (7) PM2 is downgraded to PM2_supporting. (8) Use of the Bayesian point system in curations with conflicting evidence. (9) Remove the previous location requirements (+7/-21 in BP7 and ±3/±5 in PP3) for intronic variants in BP7 and PP3. And remove the usage for UTR variants in PP3/BP4/BP7.

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Myeloid Malignancy VCEP

Released

9/15/2021

05:00:00

Rules for RUNX1

Gene: RUNX1 (HGNC:10471) HGNC Name: RUNX family transcription factor 1 Transcripts: NM_001754.4 (RUNX1c) Disease: hereditary thrombocytopenia and hematologic cancer predisposition syndrome (MONDO:0011071)

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Modification Type: Gene-specific Strong Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Modification Type: Gene-specific,Strength Moderate Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Modification Type: Disease-specific,Strength Supporting Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Modification Type: None Moderate Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. Modification Type: Strength Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Strong Moderate Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point. Moderate = 1.0 points total. Modification Type: Disease-specific,Strength Supporting Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point. Supporting = 0.5 points total. Modification Type: Disease-specific,Strength Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1. Modification Type: Gene-specific Moderate Transactivation assays demonstrating altered transactivation (<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function. Modification Type: Gene-specific,Strength Supporting Transactivation assays demonstrating enhanced transactivation (>115% of wt). Modification Type: Gene-specific,Strength Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong ≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria. Modification Type: Disease-specific Moderate 2-3 probands meeting at least one of the RUNX1-phenotypic criteria. Modification Type: Disease-specific,Strength Supporting 1 proband meeting at least one of the RUNX1-phenotypic criteria. Modification Type: Disease-specific,Strength Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Variant affecting one of the following amino acid residues within he RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. Modification Type: Gene-Specific Supporting Variant affecting one of the other amino acid residues 89-204 within the RHD. Modification Type: Gene-specific,Strength Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Variant must be completely absent from all population databases. Modification Type: Strength Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: FPD/AML is inherited in an autosomal dominant manner, thus PM3 is not applicable.
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. Modification Type: Gene-specific Supporting In-frame deletion/insertion impacting at least one of the other amino acid residues 89-204 within the RHD. Modification Type: Gene-specific,Strength Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before. Not applicable in combination with PM1. Modification Type: Strength Moderate Missense change at an amino acid residue where a different missense change which has been determined to be pathogenic before. Modification Type: None Supporting Missense change at an amino acid residue where a different missense change which has been determined to be likely pathogenic before. PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4). Modification Type: Strength Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong Moderate Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point. Moderate = 1.0 points total. Modification Type: Disease-specific,Strength Supporting Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong ≥ 7 meioses observed within one or across multiple families. Modification Type: Disease-specific,Strength Moderate Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families. Modification Type: Disease-specific,Strength Supporting 3 or 4 meioses observed within one or across multiple families. Modification Type: Disease-specific Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: The recommended cutoff for PP2 by the SVI is a missense constraint z score of 3.09 which was not met by RUNX1 (2.48 on ExAC and 2.08 on gnomAD). In addition, there are 9 benign/likely benign missense RUNX1 variants in ClinVar.
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL score ≥ 0.88. For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites. Modification Type: Gene-specific,Disease-specific Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: The FPD/AML phenotype is rather unspecific and can be caused by a number of other inherited predisposition syndromes, somatic mutations or environmental factors that are insufficient to meet the original ACMG/AMP rule PP4.
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles. Modification Type: Disease-specific Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles. Modification Type: Disease-specific Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: BS2 is not applicable since FPD/AML patients display incomplete penetrance and the average age of onset of hematologic malignancies is 33.
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Transactivation assays demonstrating normal transactivation (80- 115% of wt) AND data from a secondary assay demonstrating normal function. Modification Type: Gene-specific Moderate Supporting Transactivation assays demonstrating normal transactivation (80- 115% of wt). Modification Type: Gene-specific,Strength Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Applied when seen in ≥ 2 informative meioses. Modification Type: General recommendation Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: BP1 is not applicable for RUNX1, because both truncating and missense variants cause FPD/AML.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Modification Type: None Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: RUNX1 does not contain a repetitive region without known function. BP3 is therefore deemed not applicable.
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting For missense variants: REVEL score <0.50 AND SpliceAI ≤ 0.20. For synonymous and Intronic variants: SpliceAI ≤ 0.20. Modification Type: Gene-specific,Disease-specific Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: BP5 is not applicable. In rare circumstances, a patient can carry two pathogenic variants in genes predisposing to hematologic malignancies.
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved phyloP100 way (GRCh38/hg38) ≤2.0). Modification Type: Gene-specific,Disease-specific Not Applicable