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.
For general information about the ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding content correction or adding a new criteria specification refer to the Help page.
Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know by contacting us via email.
Release notes v1.2
• Updated verbiage from PVS1_O_Strength and BP7_O_Strength - Update: PVS1_Strength(RNA) and BP7_Strength(RNA)
• Updated verbiage to clarify: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).
• Update verbiage to clarify : Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply
• Add same verbiage as PALB2 rules: Apply to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS[RNA] is applied based on high quality observed splicing impact and must be NMD prone
• Update typo: Update to: Do not use: ATM does not have a defined low rate of missense benign variation
• Clarify in silico predictor verbiage (PP3/BP4 RNA details)
• Update 1 VS + 1 supporting (not just PM2_supporting) reaches likely pathogenic
• Updated PS1 tables to splicing group SVI tables
• Added the supplementary tables from original rules that did not transfer into the CSPEC editor.
| Criteria & Strength Specifications
|
||||
|---|---|---|---|---|
| PVS1 | ||||
|
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
Use ATM PVS1 Decision Tree
Modification Type:
Gene-specific,Strength
Strong
Use ATM PVS1 Decision Tree.
Modification Type:
Gene-specific,Strength
Moderate
Use ATM PVS1 Decision Tree.
Modification Type:
Gene-specific,Strength
Supporting
Use ATM PVS1 Decision Tree
Modification Type:
Gene-specific,Strength
Instructions:
Use ATM PVS1 Decision Tree. Not Applicable
Comments:
Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.
|
||||
| PS1 | ||||
|
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
Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.
Modification Type:
General recommendation
Moderate
Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.
Modification Type:
General recommendation,Strength
Supporting
Instructions:
Use as ascribed for protein changes as long as a splice defect is ruled out for both variants; Use Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205) Not Applicable
|
||||
| PS2 | ||||
|
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
Supporting
Not Applicable
|
||||
| PS3 | ||||
|
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
Do not use as strong.
Modification Type:
Gene-specific
Moderate
Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.
Modification Type:
Gene-specific,Strength
Supporting
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Modification Type:
Gene-specific,Strength
Instructions:
For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_Strength(RNA) and modulate strength based on assay quality and quantity (curator discretion). Not Applicable
Comments:
Conflicting functional studies should not be given any weight.
|
||||
| PS4 | ||||
|
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
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).
Modification Type:
General recommendation
Moderate
Do not use for proband counting.
Modification Type:
Disease-specific,Gene-specific
Supporting
Instructions:
Do not use for 'proband counting' method. Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). Not Applicable
|
||||
| PM1 | ||||
|
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
Supporting
Not Applicable
|
||||
| PM2 | ||||
|
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
Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply
Modification Type:
Gene-specific,Strength
Instructions:
Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply Not Applicable
Comments:
PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.
|
||||
| PM3 | ||||
|
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
Use ATM PM3/BP2 table.
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Strong
Use ATM PM3/BP2 table.
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Moderate
Use ATM PM3/BP2 table.
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Supporting
Use ATM PM3/BP2 table
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Instructions:
Use ATM PM3/BP2 table. Not Applicable
Comments:
Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).
|
||||
| PM4 | ||||
|
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
Use for stop-loss variants.
Modification Type:
General recommendation,Gene-specific
Supporting
Instructions:
Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only. Not Applicable
|
||||
| PM5 | ||||
|
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
Moderate
Supporting
Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants
Modification Type:
Gene-specific,Strength
Instructions:
Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants Not Applicable
Comments:
No rescue splicing isoforms have been identified in ATM.
|
||||
| PM6 | ||||
|
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
|
||||
| PP1 | ||||
|
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
Moderate
Supporting
Not Applicable
Comments:
Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.
|
||||
| PP2 | ||||
|
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:
Do not use: ATM does not have a defined low rate of missense benign variation.
|
||||
| PP3 | ||||
|
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
Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing
Modification Type:
Gene-specific
Instructions:
Protein: REVEL >.7333 RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing
Not Applicable
Comments:
Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.
|
||||
| PP4 | ||||
|
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 | ||||
|
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
Filtering Allele Frequency >.5%.
Modification Type:
Disease-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
Filtering Allele Frequency >.5%. Not Applicable
Comments:
FAF is a statistical model that accounts for population size and founder populations.
|
||||
| BS1 | ||||
|
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
Filtering Allele Frequency >.05%.
Modification Type:
Disease-specific
Moderate
Supporting
Instructions:
Filtering Allele Frequency >.05%. Not Applicable
Comments:
FAF is a statistical model that accounts for population size and founder populations.
|
||||
| BS2 | ||||
|
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 | ||||
|
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
Moderate
Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Modification Type:
Disease-specific,Gene-specific,Strength
Instructions:
For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_RNA and modulate strength based on assay quality and quantity (curator discretion). Not Applicable
|
||||
| BS4 | ||||
|
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
Moderate
Supporting
Not Applicable
Comments:
AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770)
. AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
|
||||
| BP1 | ||||
|
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 | ||||
|
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
Use ATM PM3/BP2 table.
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Moderate
Use ATM PM3/BP2 table.
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Supporting
Use ATM PM3/BP2 table
Modification Type:
Disease-specific,General recommendation,Gene-specific,Strength
Instructions:
Use ATM PM3/BP2 table. Not Applicable
Comments:
Multiple such cases are additive, age considerations (>18yo) are required. Observations in cis are not applicable. Source information is considered (laboratory vs database setting).
|
||||
| BP3 | ||||
|
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 | ||||
|
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
Modification Type:
General recommendation
Instructions:
Protein: REVEL <.249; RNA: multiple in silico predictors agree to a lack of splice defect. Not Applicable
|
||||
| BP5 | ||||
|
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 | ||||
|
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
Can be considered for BP7_(RNA) with curator discretion of quality.
Modification Type:
General recommendation
Moderate
Can be considered for BP7_(RNA) with curator discretion of quality.
Modification Type:
General recommendation
Supporting
Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively
Modification Type:
General recommendation
Instructions:
Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Use as BP7_(RNA) for synonymous and intronic variants with no splice defect observed. Weight for BP7_(RNA) is variable based on curator impression fo assay quality (not specified). Not Applicable
Comments:
BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.
|
||||
One Baylor Plaza, MS:BCM225 Suite 400D, Houston, TX, 77030
Questions or comments?
