owencqueen/cgbench_data huggingface dataset:
Gene: TP53 (HGNC:11998)
Evidence Code: PVS1 — Strong
Modification Type: Disease-specific,Strength
See PVS1 flowchart for code application
Gene: TP53 (HGNC:11998)
Evidence Code: PVS1 — Moderate
Modification Type: Disease-specific,Strength
See PVS1 flowchart for code application
Gene: TP53 (HGNC:11998)
Evidence Code: PS1 — Strong
Modification Type: Disease-specific,Strength
Can be applied to variants asserted as Pathogenic following the 
TP53
 VCEP’s specifications.
Gene: TP53 (HGNC:11998)
Evidence Code: PS1 — Moderate
Modification Type: Disease-specific,Strength
Can be applied to variants asserted as Likely Pathogenic following the 
TP53
 VCEP’s specifications.
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Very Strong
Modification Type: Disease-specific,Strength
≥ 8 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Strong
Modification Type: Disease-specific,Strength
4-7 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Moderate
Modification Type: Disease-specific,Strength
2-3 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Supporting
Modification Type: Disease-specific,Strength
1 point
Gene: TP53 (HGNC:11998)
Evidence Code: PS3 — Strong
Modification Type: Disease-specific,Strength
Non-functional on Kato et al. data 
AND
 loss of function (LOF) on Giacomelli et al. data 
AND/OR
 LOF on another assay (e.g. Kotler or a second assay showing low function)
Gene: TP53 (HGNC:11998)
Evidence Code: PS3 — Moderate
Modification Type: Disease-specific,Strength
Partially functional on Kato et al. data 
AND
 loss of function (LOF) on Giacomelli et al. data 
AND/OR
 LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3_Moderate if any assay evidence is conflicting.
Gene: TP53 (HGNC:11998)
Evidence Code: PS3 — Supporting
Modification Type: Disease-specific,Strength
Non-functional on Kato et.al data 
AND
 abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data 
AND
 LOF (or no data available) on Giacomelli et al. data.


PS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Very Strong
Modification Type: Disease-specific,Strength
≥ 8 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Strong
Modification Type: Disease-specific,Strength
≥ 4-7.5 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Moderate
Modification Type: Disease-specific,Strength
2-3.5 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Supporting
Modification Type: Disease-specific,Strength
1-1.5 points
Gene: TP53 (HGNC:11998)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific,Strength
Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.
Gene: TP53 (HGNC:11998)
Evidence Code: PM1 — Supporting
Modification Type: Disease-specific,Strength
Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.
Gene: TP53 (HGNC:11998)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,General recommendation
This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be <0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. 


If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) 
AND
 has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.0004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2_Supporting can be met.


In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)
Gene: TP53 (HGNC:11998)
Evidence Code: PM5 — Strong
Modification Type: Disease-specific,Strength
Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the 
TP53
 VCEP’s specifications have been seen before.
Gene: TP53 (HGNC:11998)
Evidence Code: PM5 — Moderate
Modification Type: Disease-specific,Strength
Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the 
TP53
 VCEP’s specifications has been seen before.
Gene: TP53 (HGNC:11998)
Evidence Code: PM5 — Supporting
Modification Type: Disease-specific,Strength
Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the 
TP53
 VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5_Supporting code application.
Gene: TP53 (HGNC:11998)
Evidence Code: PP1 — Moderate
Modification Type: Disease-specific,Strength
Cosegregation must be observed in 5-6 meioses in/across 1 or more families
Gene: TP53 (HGNC:11998)
Evidence Code: PP1 — Supporting
Modification Type: Disease-specific,Strength
Cosegregation must be observed in 3-4 meioses in/across 1 or more families
Gene: TP53 (HGNC:11998)
Evidence Code: PP3 — Supporting
Modification Type: Disease-specific,Strength
Missense variants
 
(See flowchart for application of PP3 and BP4 rules for missense variants)


aGVGD class C25-C55 and BayesDel score ≥ 0.16


Single amino acid inframe deletions
 
(See single aa BayesDel spreadsheet)


BayesDel score ≥ 0.16


Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):


SpliceAI ≥ 0.2
Gene: TP53 (HGNC:11998)
Evidence Code: PP4 — Moderate
Modification Type: Disease-specific,Strength
At least 2 independent observations of the variant with VAF 5-25%.
Gene: TP53 (HGNC:11998)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific,Strength
Observation of the variant with VAF at or below 35%.
Gene: TP53 (HGNC:11998)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ("allele balance" in gnomAD) below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. 


In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)
Gene: TP53 (HGNC:11998)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. 


In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)
Gene: TP53 (HGNC:11998)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.
Gene: TP53 (HGNC:11998)
Evidence Code: BS2 — Moderate
Modification Type: Disease-specific
4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.
Gene: TP53 (HGNC:11998)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific
2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.
Gene: TP53 (HGNC:11998)
Evidence Code: BS3 — Strong
Modification Type: Disease-specific,Strength
Functional on Kato et al. data 
AND
 no loss of function (LOF) on Giacomelli et al. data 
AND/OR
 no evidence of LOF on another assay (e.g. Kotler or a second assay)
Gene: TP53 (HGNC:11998)
Evidence Code: BS3 — Supporting
Modification Type: Disease-specific,Strength
Partially functional on Kato et al. data 
AND
 no evidence of loss of function (LOF) on Giacomelli et al. data 
AND
 no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) 
AND
 normal or no data on Kawaguchi et al. data. Do not apply BS3_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data 
AND
 no evidence of LOF (or no data available) on Giacomelli et al. data. 


BS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.
Gene: TP53 (HGNC:11998)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).
Gene: TP53 (HGNC:11998)
Evidence Code: BP4 — Moderate
Modification Type: Disease-specific,Strength
Missense variants
 
(See flowchart for application of PP3 and BP4 rules for missense variants):


BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4_Moderate) AND no predicted differences in splicing (SpliceAI < 0.2)
Gene: TP53 (HGNC:11998)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific,Strength
Missense variants
 
(See flowchart for application of PP3 and BP4 rules for missense variants):


BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)


Single amino acid inframe deletions
 
(See single aa BayesDel spreadsheet):


BayesDel score < 0.16 AND no predicted splicing impact (Splice AI < 0.2)


Silent or Intronic Variants (outside ± 1,2 positions):


SpliceAI ≤ 0.1
Gene: TP53 (HGNC:11998)
Evidence Code: BP7 — Strong
Modification Type: Disease-specific
A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.
Gene: TP53 (HGNC:11998)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met.