owencqueen/cgbench_data huggingface dataset:
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 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 
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 — Strong
Modification Type: Gene-specific,Strength
2-3.5 
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
1-1.5 
de novo
 score. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PS3 — Moderate
Modification Type: Gene-specific,Strength
RNA assays
 show 




a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
OR


inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
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 exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
OR


over-expression of an alternative transcript (exons 10, 11 or 15)




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 — Strong
Modification Type: Gene-specific,Strength
4-15.5 phenotype points. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Moderate
Modification Type: Gene-specific,Strength
2-3.5 phenotype points. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PS4 — Supporting
Modification Type: Gene-specific,Strength
1-1.5 phenotype point. For phenotype points curation see 
Table 1
.
Gene: APC (HGNC:583)
Evidence Code: PM2 — Supporting
Modification Type: Gene-specific,Strength
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.
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 — Strong
Modification Type: Gene-specific,Strength
2-3.5 
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
1-1.5 
de novo
 scores. For curation of 
de novo
 score see 
Tables 1
 and 
2
.
Gene: APC (HGNC:583)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Variant segregates in 3-4 meioses in ≥ 1 family.
Gene: APC (HGNC:583)
Evidence Code: PP3 — Supporting
Modification Type: Gene-specific,Strength
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: BA1 — Stand Alone
Modification Type: Gene-specific
GnomAD Popmax Filtering Allele Frequency (AF) 
≥ 0.1%
 (0.001).
Gene: APC (HGNC:583)
Evidence Code: BS1 — Strong
Modification Type: Gene-specific
GnomAD Popmax Filtering Allele Frequency (AF) 
≥ 0.001%
 (0.00001).
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


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, 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)
Gene: APC (HGNC:583)
Evidence Code: BP1 — Supporting
Modification Type: No change
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) [Reference 3].