owencqueen/cgbench_data huggingface dataset:
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PS1 — Strong
Modification Type: General recommendation
Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points).
Gene: VHL (HGNC:12687)
Evidence Code: PS2 — Strong
Modification Type: Strength
Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 
de novo
 points).
Gene: VHL (HGNC:12687)
Evidence Code: PS2 — Moderate
Modification Type: General recommendation,Strength
Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 
de novo
 points)
Gene: VHL (HGNC:12687)
Evidence Code: PS2 — Supporting
Modification Type: Strength
Phenotype consistent but not highly specific (≥0.5 but less than 1 
de novo
 points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
Acceptable assays that display functional effect in VHL are the following:  


• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or 


• VBC complex stability is affected and/or


• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding 
1
 , 
2
 , 
3
 , 
17


Multiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B.  VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3_Supporting and 11 for PS3_Moderate 
10
. We propose to 
follow the workflow outlined in Brnich et al.
  Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. 


SPLICING:
 
PS3:
 RNA transcripts carrying splicing mutation display splicing defects in patient cells. 
PS3_Moderate
: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays.   
Functional Assay Documentation
 : 
https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific,Strength
16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.
Gene: VHL (HGNC:12687)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific,Strength
5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.
Gene: VHL (HGNC:12687)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Strength
2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.
Gene: VHL (HGNC:12687)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Strength
1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific
Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.
Gene: VHL (HGNC:12687)
Evidence Code: PM1 — Supporting
Modification Type: Strength
Putative missense variants seen in somatic databases, having <10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,Strength
PM2_Supporting can be applied for variants either absent from gnomAD or with <= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2_Supporting may also be applied.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PM4 — Moderate
Modification Type: Disease-specific
In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL 
15
 cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease).  The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). 


PM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PM5 — Moderate
Modification Type: General recommendation
Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 
16
 ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing.
Gene: VHL (HGNC:12687)
Evidence Code: PM6 — Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Gene: VHL (HGNC:12687)
Evidence Code: PM6 — Moderate
Modification Type: Disease-specific,General recommendation
See PS2 evidence code for scoring and phenotypes. Assumed 
de novo
 receives half the points as compared to maternity and paternity confirmed 
de novo
. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PP1 — Strong
Modification Type: Strength
>7 meioses across >=2 families
Gene: VHL (HGNC:12687)
Evidence Code: PP1 — Moderate
Modification Type: Strength
5 – 6 meioses across ≥1 family.
Gene: VHL (HGNC:12687)
Evidence Code: PP1 — Supporting
Modification Type: General recommendation
3 – 4 meioses across ≥1 family.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific
For missense variants, use REVEL score >=0.664. 


For splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5).
Gene: VHL (HGNC:12687)
Evidence Code: PP4 — Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BA1 — Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Gene: VHL (HGNC:12687)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release).
Gene: VHL (HGNC:12687)
Evidence Code: BS1 — Original ACMG Summary
Allele frequency is greater than expected for disorder.
Gene: VHL (HGNC:12687)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Use BS1 cut off of  >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4).
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
VHL is not highly penetrant 
at an early age.
 BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
with full phenotyping and screening
 for the absence of VHL-related cancers.
Gene: VHL (HGNC:12687)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific
VHL is not highly penetrant 
at an early age.
 BS2_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
lacking full phenotyping and screening
, with no noted VHL-related cancers
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific
• HIF 1/2a assay replicates WT function and/or


• VBC complex stability is not affected and/or 


• ECM formation/fibronectin binding is unaffected 


This rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BS4 — Strong
Modification Type: General recommendation
Lack of segregation is seen in affected members of ≥2 families
Gene: VHL (HGNC:12687)
Evidence Code: BS4 — Supporting
Modification Type: General recommendation
Lack of segregation is seen in 1 family.
Gene: VHL (HGNC:12687)
Evidence Code: BP1 — Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BP2 — Strong
Modification Type: Disease-specific
i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)


ii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia


iii) -OR observed 
in cis
 or with unknown phase with three or more different pathogenic 
VHL
 variants
Gene: VHL (HGNC:12687)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
-variant is observed 
in cis
 (or phase is unknown) w/ a pathogenic 
VHL
 variant
Gene: VHL (HGNC:12687)
Evidence Code: BP3 — Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Gene: VHL (HGNC:12687)
Evidence Code: BP3 — Supporting
Modification Type: Disease-specific
BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. 


BP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2).
Gene: VHL (HGNC:12687)
Evidence Code: BP5 — Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
Gene: VHL (HGNC:12687)
Evidence Code: BP5 — Supporting
Modification Type: Disease-specific
BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a 
VHL
 variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the 
VHL
 variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a 
VHL
 variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease.
Gene: VHL (HGNC:12687)
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: VHL (HGNC:12687)
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: VHL (HGNC:12687)
Evidence Code: BP7 — Supporting
Modification Type: General recommendation
To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.