Re-evaluation proposal for variant pathogenicity scores

 
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Variant Gene HGVS variant name (c.)
 
ACMG/AMP Classification (Richards & al)
Evidence of pathogenicity Category     Evidence of benign Category  
Very strong
Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease

PVS1 null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where 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
Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

BA1 Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change

PS1 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

Strong
Allele frequency is greater than expected for disorder

BS1 Allele frequency is greater than expected for disorder

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history

PS2 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, and so on, can contribute to nonmaternity.

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

BS2 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

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product

PS3 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.

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing

BS3 Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls

PS4 The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls

Note 1: Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article 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.

Lack of segregation in affected members of a family

BS4 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.

Moderate
Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation

PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation

Supporting
Missense variant in a gene for which primarily truncating variants are known to cause disease

BP1 Missense variant in a gene for which primarily truncating variants are known to cause disease

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

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

BP2 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

For recessive disorders, detected in trans with a pathogenic variant

PM3 For recessive disorders, detected in trans with a pathogenic variant

Note: This requires testing of parents (or offspring) to determine phase

In-frame deletions/insertions in a repetitive region without a known function

BP3 In-frame deletions/insertions in a repetitive region without a known function

Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants

PM4 Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)

BP4 Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)

Caveat: Because 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.

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before

PM5 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.

Variant found in a case with an alternate molecular basis for disease

BP5 Variant found in a case with an alternate molecular basis for disease

Assumed de novo, but without confirmation of paternity and maternity

PM6 Assumed de novo, but without confirmation of paternity and maternity

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation

BP6 Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation

Supporting
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease

PP1 Cosegregation 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

A synonymous (silent) 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

BP7 A synonymous (silent) 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

Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease

PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease

Uncertain significance: Not enough evidence
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)

PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)

Caveat: Because 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.

Comment, additional information, DOI, etc.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

PP4 Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation

PP5 Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation

PubMed PMID (PMID1;PMID2;etc.)
 
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