owencqueen/cgbench_data huggingface dataset:
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PVS1 — Very Strong
Modification Type: Gene-specific,Strength
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
Figure 1
) [Reference 1].
Gene: APC (HGNC:583)
Evidence Code: PVS1 — Strong
Modification Type: Gene-specific,Strength
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
Figure 1
) [Reference 1].
Gene: APC (HGNC:583)
Evidence Code: PVS1 — Moderate
Modification Type: Gene-specific,Strength
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
Figure 1
) [Reference 1].
Gene: APC (HGNC:583)
Evidence Code: PVS1 — Supporting
Modification Type: Gene-specific,Strength
Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
Figure 1
) [Reference 1].
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PS1 — Strong
Modification Type: Gene-specific,Strength
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 (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 
1
 or similar to the previously established variant by multiple 
in silico
 predictors.


1
 See Supplemental material - Evaluation of canonical ±1 or 2 splice sites
Gene: APC (HGNC:583)
Evidence Code: PS1 — Moderate
Modification Type: Gene-specific,Strength
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 
1
 or similar to the previously established variant by multiple 
in silico
 predictors.


1
 See Supplemental material - Evaluation of canonical ±1 or 2 splice sites
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PS2 — Very Strong
Modification Type: Gene-specific,Strength
≥ 4 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PS2 — Strong
Modification Type: Gene-specific,Strength
2-3 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PS2 — Moderate
Modification Type: Gene-specific,Strength
1 
de novo
 score. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PS3 — Very Strong
Modification Type: Gene-specific,Strength
RNA assays
 show




a premature stop codon
OR


inframe skipping of exon 13 or 14




AND
 the absence of full-length transcript.
Gene: APC (HGNC:583)
Evidence Code: PS3 — Strong
Modification Type: Gene-specific,Strength
RNA assays
 show




a premature stop codon
OR


inframe skipping of exon 13 or 14




AND
 < 10% of full-length transcript.
Gene: APC (HGNC:583)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
RNA assays
 show 




a premature stop codon
OR


inframe skipping of exon 13 or 14
OR


other inframe skipping AND absent or < 10% full-length transcript.
Gene: APC (HGNC:583)
Evidence Code: PS3 — Supporting
Modification Type: Gene-specific,Strength
RNA assays
 show 




inframe skipping of of exons other than exon 13 or 14
OR


over-expression of an alternative transcript




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].
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Very Strong
Modification Type: Gene-specific,Strength
≥ 16 phenotype points. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Strong
Modification Type: Gene-specific,Strength
4-15 phenotype points. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Moderate
Modification Type: Gene-specific,Strength
2-3 phenotype points. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Supporting
Modification Type: Gene-specific,Strength
1 phenotype point. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific,Strength
Rare in controls is defined by an allele frequency ≤ 0.0003% (0.000003).
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PM4 — Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PM5 — Moderate
Modification Type: Gene-specific,Strength
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].
Gene: APC (HGNC:583)
Evidence Code: PM5 — Supporting
Modification Type: Gene-specific,Strength
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].
Gene: APC (HGNC:583)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: APC (HGNC:583)
Evidence Code: PM6 — Strong
Modification Type: Gene-specific,Strength
2-3 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PM6 — Moderate
Modification Type: Gene-specific,Strength
1 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PM6 — Supporting
Modification Type: Gene-specific,Strength
0.5 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PP1 — Strong
Modification Type: Strength
Variant segregates in ≥ 7 meioses in ≥ 2 families.
Gene: APC (HGNC:583)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Variant segregates in 5-6 meioses in ≥ 1 family.
Gene: APC (HGNC:583)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Variant segregates in 3-4 meioses in ≥ 1 familiy.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific,Strength
This criterion can be applied to missense and non-canonical splicing variants.


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.
Gene: APC (HGNC:583)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: APC (HGNC:583)
Evidence Code: BA1 — Stand Alone
Modification Type: Gene-specific
Allele frequency 
≥ 0.1%
 (0.001).
Gene: APC (HGNC:583)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: APC (HGNC:583)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
Allele frequency 
≥ 0.001%
 (0.00001).
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BS2 — Strong
Modification Type: Gene-specific,Strength
≥ 10 points for healthy individuals 
OR
 ≥ 2 times in homozygous state.


A 
healthy individual
 worth 1 point is defined by:


Age ≥ 50 years 
+ Less than 5 adenomatous polyps in a colonoscopy 
+ Absence of features in Table 1


OR


Age ≥ 50 years 
+ Colorectal cancer/polyposis was not the indication for testing


A 
healthy individual
 worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.
Gene: APC (HGNC:583)
Evidence Code: BS2 — Supporting
Modification Type: Gene-specific,Strength
≥ 3 points for healthy individuals.


A 
healthy individual
 worth 1 point is defined by:


Age ≥ 50 years 
+ Less than 5 adenomatous polyps in a colonoscopy 
+ Absence of features in Table 1


OR


Age ≥ 50 years 
+ Colorectal cancer/polyposis was not the indication for testing


A 
healthy individual
 worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.
Gene: APC (HGNC:583)
Evidence Code: BS3 — Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Gene: APC (HGNC:583)
Evidence Code: BS3 — Strong
Modification Type: Gene-specific,Strength
RNA assay
 of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration


AND


if biallelic expression is shown and/or nonsense-mediated decay inhibition was used.
Gene: APC (HGNC:583)
Evidence Code: BS3 — Supporting
Modification Type: Gene-specific,Strength
RNA assay
 of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration


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)
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BS4 — Strong
Modification Type: Gene-specific,Strength
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
).
Gene: APC (HGNC:583)
Evidence Code: BS4 — Supporting
Modification Type: Gene-specific,Strength
Affected member without the variant must score at least 0.5 phenotype points (see 
Table 1
).
Gene: APC (HGNC:583)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: APC (HGNC:583)
Evidence Code: BP1 — Supporting
Modification Type: No change
Exception: not applicable to missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) [Reference 3].
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BP2 — Supporting
Modification Type: Gene-specific
Observed 
in trans
 with a (Likely) Pathogenic 
APC
 variant 
OR
 ≥ 3 times in an unknown phase with different (Likely) Pathogenic 
APC
 variants.
Gene: APC (HGNC:583)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BP4 — Supporting
Modification Type: Gene-specific
Missense variants:
 BP4 is not applicable.


Synonymous (silent) or intronic variants
: Multiple in silico splicing predictors suggest no impact on gene or gene product.
Gene: APC (HGNC:583)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: APC (HGNC:583)
Evidence Code: BP5 — Supporting
Modification Type: No change
Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: 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.
Gene: APC (HGNC:583)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
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.