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.
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- Correction of some inaccuracies in the Rules for Combining Criteria.
- Addition of some relevant instructions out of the supplementary material
- Change in Fig. 1A: Update of the possible pathways for “G to non-G changes”
- Change in Fig. 1B: Transfer of splice variants c.136-1G>A,C,T; c.136-2A>C,G,T; c.220+1G>A,C,T and c.220+2T>A,C,G from List E to List A and transfer of c.220G>A,C,T from List E to List B based on RNA and phenotype data
- Update of the supplementary material file.
Criteria & Strength Specifications
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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
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1].
Modification Type:
Gene-specific,Strength
Strong
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1].
Modification Type:
Gene-specific,Strength
Moderate
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1].
Modification Type:
Gene-specific,Strength
Supporting
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1].
Modification Type:
Gene-specific,Strength
Not Applicable
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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
The previously established variant was classified as Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in APC. Missense variants: when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. Splice variants: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple in silico predictors.
Modification Type:
Gene-specific,Strength
Moderate
The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in APC. Missense variants: when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. Splice variants: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple in silico predictors.
Modification Type:
Gene-specific,Strength
Supporting
Instructions:
Recommended splice prediction programs:
For SpliceAI a loss of the native splice site is considered for scores between 0.8 and 1. A gain of a cryptic splice site is considered strong for scores between 0.8 and 1 and as moderate for a score between 0.2 and 0.8. For MaxEntScan predictions a score of >3 is required for credibility of a native site prediction and a threshold of -15% is considered for native splice site loss (Houdayer et al. 2012, PMID 22505045). A score >3 is used as a conservative measure for cryptic site use in the context of native site loss. Not Applicable
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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
≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Strong
2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Moderate
1-1.5 de novo score. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Supporting
Not Applicable
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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
RNA assays show
AND the absence of full-length transcript.
Modification Type:
Gene-specific,Strength
Strong
RNA assays show
AND < 10% of full-length transcript.
Modification Type:
Gene-specific,Strength
Moderate
RNA assays show
Modification Type:
Gene-specific,Strength
Supporting
RNA assays show
Protein assays show Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of APC) [Reference 2].
Modification Type:
Gene-specific,Strength
Not Applicable
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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
≥ 16 phenotype points. For phenotype points curation see Table 1.
Modification Type:
Gene-specific,Strength
Strong
4-15.5 phenotype points. For phenotype points curation see Table 1.
Modification Type:
Gene-specific,Strength
Moderate
2-3.5 phenotype points. For phenotype points curation see Table 1.
Modification Type:
Gene-specific,Strength
Supporting
1-1.5 phenotype point. For phenotype points curation see Table 1.
Modification Type:
Gene-specific,Strength
Not Applicable
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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
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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
Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1.
Modification Type:
Gene-specific,Strength
Instructions:
General recommendation: Use the total population from the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
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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
Strong
Moderate
Supporting
Not Applicable
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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
Supporting
Not Applicable
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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
The reported missense variant was determined to be Pathogenic according to the APC-specific modifications. There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].
Modification Type:
Gene-specific,Strength
Supporting
The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications. There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].
Modification Type:
Gene-specific,Strength
Not Applicable
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PM6 | ||||
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Strong
2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Moderate
1-1.5 de novo scores. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Supporting
0.5 de novo scores. For curation of de novo score see Tables 1 and 2.
Modification Type:
Gene-specific,Strength
Instructions:
PM6_VeryStrong: ≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. Not Applicable
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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
Variant segregates in ≥ 7 meioses in ≥ 2 families.
Modification Type:
Strength
Moderate
Variant segregates in 5-6 meioses in ≥ 1 family.
Modification Type:
Strength
Supporting
Variant segregates in 3-4 meioses in ≥ 1 family.
Modification Type:
Strength
Instructions:
Affected individuals exhibit at least 0.5 point of the phenotype point system (see Table 1), for relatives also ≥ 10 or “multiple” colorectal adenomas are considered as 0.5 point. Only genotype and phenotype positive individuals and obligate carriers with phenotype are counted (note: carriers who have received chemoprevention and may have a milder phenotype can also be counted). Not Applicable
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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
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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
Missense variants: Do not use computational prediction models for conservation, evolution, etc. In silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants: Multiple in silico splicing predictors support a deleterious effect.
Modification Type:
Gene-specific,Strength
Instructions:
Recommended splice prediction programs: see PS1 Not Applicable
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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
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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
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BA1 | ||||
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.1% (0.001).
Modification Type:
Gene-specific
Very Strong
Strong
Moderate
Supporting
Instructions:
General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
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BS1 | ||||
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.001% (0.00001).
Modification Type:
Gene-specific
Moderate
Supporting
Instructions:
General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
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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
≥ 10 points for healthy individuals OR ≥ 2 times in homozygous state. A healthy individual worth 1 point is defined by: Age ≥ 50 years OR Age ≥ 50 years A healthy individual worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.
Modification Type:
Gene-specific,Strength
Moderate
Supporting
≥ 3 points for healthy individuals. A healthy individual worth 1 point is defined by: Age ≥ 50 years OR Age ≥ 50 years A healthy individual worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.
Modification Type:
Gene-specific,Strength
Instructions:
The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals. Not Applicable
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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
RNA assay of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration AND biallelic expression is shown and/or nonsense-mediated decay inhibition was used.
Modification Type:
Gene-specific,Strength
Moderate
Supporting
RNA assay of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition OR Protein assay show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of APC, see PMID: 33348689)
Modification Type:
Gene-specific,Strength
Not Applicable
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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
Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see Table 1).
Modification Type:
Gene-specific,Strength
Moderate
Supporting
Affected member without the variant must score at least 0.5 phenotype points (see Table 1).
Modification Type:
Gene-specific,Strength
Not Applicable
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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
BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035).
Modification Type:
No change
Instructions:
A number of assumed “missense” variants are in fact splice variants. At least several splice prediction tools should be used. Recommended splice prediction programs: see PS1 Not Applicable
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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
Moderate
Supporting
Observed in trans with a (Likely) Pathogenic APC variant OR ≥ 3 times in an unknown phase with different (Likely) Pathogenic APC variants.
Modification Type:
Gene-specific
Not Applicable
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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
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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
Missense variants: BP4 is not applicable. Synonymous (silent) or intronic variants: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Modification Type:
Gene-specific
Instructions:
Recommended splice prediction programs: see PS1 Not Applicable
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BP5 | ||||
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.
Modification Type:
No change
Instructions:
(Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous variants in POLD1 or POLE; biallelic variants in MUTYH, NTHL1 or MSH3; in patients with onset in childhood / adolescence: biallelic variants in MLH1, MSH2, MSH6 or PMS2). This rule is only applicable when a colorectal polyposis phenotype is present. Not Applicable
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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
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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
Moderate
Supporting
A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Modification Type:
General recommendation
Instructions:
The use of BP7 with BP4 is allowed. Recommended splice prediction programs: see PS1 Not Applicable
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