Criteria Specification Registry

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Criteria Specification

ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Description : MM-VCEP ACMG/AMP specifications for RUNX1

Version : 1.0.0

PDF

Myeloid Malignancy VCEP

Released

7/10/2019

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 Null variant in a gene where LOF is a known mechanism of disease. Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Comments: RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C, meet PVS1_moderate. Strong Null variant in a gene where LOF is a known mechanism of disease. Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Comments: RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C, meet PVS1_moderate. Moderate Null variant in a gene where LOF is a known mechanism of disease. Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. Comments: RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C, meet PVS1_moderate. Supporting Instructions: Per modified RUNX1 PVS1 decision tree for SNVs, indels and CNVs and table of splicing effects. 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 AA change as a previously established pathogenic variant regardless of nucleotide change. Comments: RNA data or agreement in splicing predictors show no splicing effects (SSF and MES predict either increase in canonical splice site score or decrease of canonical splice score by no more than 10% and no putative splice site are created). The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied Moderate Same AA change as a previously established likely pathogenic variant regardless of nucleotide change. Comments: RNA data or agreement in splicing predictors show no splicing effects (SSF and MES predict either increase in canonical splice site score or decrease of canonical splice score by no more than 10% and no putative splice site are created). The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied Supporting Instructions: RNA data or agreement in splicing predictors show no splicing effects.,The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied 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 ≥ 2 proven de novo occurrences (maternity and paternity confirmed) in patients with the RUNX1-phenotype. Comments: No family history is defined as: absence of the variant and any of the RUNX1-phenotypic criteria in first- or second degree relatives. The proband must exhibit at least one phenotypic FPD/AML criterion. (3) The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules. Supporting 1 proven de novo occurrence (maternity and paternity confirmed) in a patient with the RUNX1-phenotype. Comments: No family history is defined as: absence of the variant and any of the RUNX1-phenotypic criteria in first- or second degree relatives. The proband must exhibit at least one phenotypic FPD/AML criterion. (3) The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules. Instructions: The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules.,The proband must exhibit at least one phenotypic FPD/AML criterion. 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. PS3 cannot be applied if the variant meets PVS1. If the variant meets criteria for PVS1_strong and PS3, we recommend applying either PS3_moderate or upgrading PVS1_strong to PVS1 without applying PS3 . Comments: Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays. The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo). PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products 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. Comments: Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays. The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo). PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products Supporting Transactivation assays demonstrating enhanced transactivation (>115% of wt). Comments: Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays. The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo). PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products Instructions: PS3 cannot be applied if the variant meets PVS1. If the variant meets criteria for PVS1_strong and PS3, we recommend applying either PVS1_strong and PS3_moderate or upgrading PVS1_strong to PVS1 (if undergo NMD) without applying PS3.,Transactivation assays demonstrating altered transactivation: <20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q.,PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products. 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 The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ≥ 4 probands meeting RUNX1-phenotypic criteria. Comments: The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once. Moderate The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. 2-3 probands meeting RUNX1-phenotypic criteria. Comments: The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once. Supporting The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. 1 proband meeting RUNX1-phenotypic criteria. Comments: The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once. Instructions: The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once. 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 Located in a mutational hot spot and/or critical and well-established functional domain without benign variation. Variant affecting one of the following 13 hotspot residues: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204. Comments: The RHD (AA 77-204) has been established as highly conserved DNA-binding domain without any benign variation in ClinVar. Residues in the region (AA 77-104) are also in the RHD, but no germline variants have been reported to date. The AA range under PM1_supporting may be expanded in the future to other parts of the protein if more evidence emerges. Supporting Located in a mutational hot spot and/or critical and well-established functional domain without benign variation. Variant affecting one of the other AA residues 105-204 within the RHD. Comments: The RHD (AA 77-204) has been established as highly conserved DNA-binding domain without any benign variation in ClinVar. Residues in the region (AA 77-104) are also in the RHD, but no germline variants have been reported to date. The AA range under PM1_supporting may be expanded in the future to other parts of the protein if more evidence emerges. 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 Absent from controls. Per original ACMG/AMP guidelines. Comments: Variant must be completely absent from all population databases. The mean coverage of RUNX1 in the population database used should be at least 20x. Supporting Instructions: PM2 is not considered as a conflicting evidence in a Benign/Likely Benign classification.,Variant must be completely absent from all population databases.,The mean coverage of RUNX1 in the population database used should be at least 20x. 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
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 Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. In-frame deletion/insertion impacting at least one of the 13 hotspot residues R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201 Comments: See PM1 Supporting Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Other in-frame deletion/insertion impacting residues 105-204 within the RHD. Comments: See PM1 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 the same residue where ≥ 2 different missense changes have previoulsy been determined to be pathogenic. PM5_strong cannot be applied together with PM1. Comments: see PS1 Moderate Missense change at the same residue where a different missense change has previously been determined to be pathogenic. Comments: see PS1 Supporting Missense change at the same residue where a different missense change has previously been determined to be likely pathogenic. Comments: see PS1 Instructions: RNA data or agreement in splicing predictors show no splicing effects.,The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied 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 Assumed de novo (but without confirmation of maternity and paternity) in a patient with the disease and no family history. ≥ 4 assumed de novo occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-phenotype. Comments: see PS2 Supporting Assumed de novo (but without confirmation of maternity and paternity) in a patient with the disease and no family history. 2 or 3 assumed de novo occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-phenotype. Comments: see PS2 Instructions: The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules.,The proband must exhibit at least one phenotypic FPD/AML criterion. 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 Co-segregation with disease in multiple affected family members. ≥ 7 meioses observed within one or across multiple families. Comments: Affected individuals show at least one of the RUNX1-specific phenotypic criteria. Only genotype and phenotype positive individuals and obligate carriers are counted. Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family. Moderate Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families. Comments: Affected individuals show at least one of the RUNX1-specific phenotypic criteria. Only genotype and phenotype positive individuals and obligate carriers are counted. Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family. Supporting Co-segregation with disease in multiple affected family members. 3 or 4 meioses observed within one or across multiple families. Comments: Affected individuals show at least one of the RUNX1-specific phenotypic criteria. Only genotype and phenotype positive individuals and obligate carriers are counted. Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family. Instructions: Affected individuals show at least one of the RUNX1-specific phenotypic criteria.,Only genotype and phenotype positive individuals and obligate carriers are counted.,Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family. 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
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 Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Comments: PP3 should be applied for missense variants with a REVEL score of >0.75. PP3 should also be applied for missense or synonymous variants if the variant alters the last three bases of an exon preceding a splice donor site or the first three bases of an exon following an acceptor splice site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site. PP3 should also be applied for intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for donor splice sites or -3 to -5 for acceptor splice sites and the predicted decrease in the score of the canonical splice site is at least 75% (measured by both MES and SSF) regardless of the predicted creation/presence of a putative cryptic splice site. PP3 cannot be applied for canonical splice site variants. Instructions: PP3 should be applied for missense variants with a REVEL score of >0.75,PP3 should be applied for missense or synonymous variants if the variant alters the last three bases of an exon preceding a donor splice site or the first three bases of an exon following a splice acceptor site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site.,PP3 should also be applied for intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for splice donor sites or -3 to -5 for splice acceptor sites for which the predicted decrease in the score is at least 75% (measured by both MES and SSF) regardless of the predicted creation/presence of a putative cryptic splice site.,PP3 cannot be applied if the variant meets PVS1 codes (e.g. canonical splice site variants). 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
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 Allele frequency is >5% in ESP, 1000G, or ExAC. Comments: The variant is present in in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles. Very Strong Strong Moderate Supporting Instructions: The variant is present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles. 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 Allele frequency is greater than expected for disorder. MAF between 0.00015 (0.015%) and 0.0015 (0.15%) Comments: The variant is present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles. Variant can be classified as likely benign based on BS1 alone if there is no contradictory evidence supporting pathogenicity. Moderate Supporting Instructions: Variant can be classified as likely benign based on BS1 alone if there is no contradictory evidence supporting pathogenicity.,The variant is present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles. 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
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 Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Transactivation assays demonstrating normal transactivation (80-115% of wt) AND data from a secondary assay demonstrating normal function. Comments: see PS3 (1) and (2) Moderate Supporting Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Transactivation assays demonstrating normal transactivation (80-115% of wt). Comments: see PS3 (1) and (2) Instructions: Transactivation assays demonstrating normal transactivation: 80-115% of wt 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 Lack of segregation in affected members of a family. Applied when seen in ≥ 2 informative meioses. Comments: This code should only be applied for genotype-positive, phenotype-negative (with sufficient laboratory evidence) family members. Moderate Supporting Instructions: This code should only be applied for genotype-positive, phenotype-negative (with sufficient laboratory evidence) family members. 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
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. Per original ACMG/AMP guidelines. Comments: BP2 can also be applied if the variant is detected in a homozygous state. Instructions: BP2 can also be applied if the variant is detected in a homozygous state. 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
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 Multiple lines of computational evidence suggest no impact on gene or gene product. Comments: BP4 should be applied for missense variants with a REVEL score < 0.15 as well as synonymous, intronic and non-coding variants for which SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created. Instructions: BP4 should be applied for missense variants if all of the following apply - REVEL score < 0.15.,SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10%,No putative cryptic splice sites are created. BP4 should also be applied for synonymous, intronic and non-coding variants for which SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created. 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
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 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. Per original ACMG/AMP guidelines. BP7 can not be applied in combination with PP3. Comments: Also applicable to intronic/non-coding variants at or beyond positions +7/-21 for which (1) SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created AND (2) evolutionary conservation prediction algorithms predict the site as not conserved (e.g. PhyloP score < 0.1 or the variant is the reference nucleotide in one primate and/or three mammal species.). Instructions: BP7 is also applicable to intronic/non-coding variants at or beyond positions +7/-21 for which,SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created AND,Evolutionary conservation prediction algorithms predict the site as not conserved (e.g. PhyloP score < 0.1 or the variant is the reference nucleotide in one primate and/or three mammal species.). BP7 can not be applied in combination with PP3. Not Applicable