owencqueen/cgbench_data huggingface dataset:
Gene: TP53 (HGNC:11998)
Evidence Code: PVS1 — Very Strong
Modification Type: General recommendation
Defer to SVI recommendations
Gene: TP53 (HGNC:11998)
Evidence Code: PS1 — Strong
Modification Type: Strength
Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.
Gene: TP53 (HGNC:11998)
Evidence Code: PS1 — Moderate
Modification Type: Strength
Must confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Very Strong
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Strong
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Moderate
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 1 point (for 1 cancer from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PS2 — Supporting
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
0.5 point (1 cancer from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PS3 — Strong
Modification Type: Strength
Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:




Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data
  OR 


There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays)
Do not use code with conflicting evidence
Gene: TP53 (HGNC:11998)
Evidence Code: PS3 — Moderate
Modification Type: Strength
(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:




Evidence of DNE + evidence of LOF from Giacomelli, et al data.
  OR 


There is a 2nd assay showing low function.
 Do not use code with conflicting evidence.
 (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:


Evidence of DNE + evidence of LOF from Giacomelli, et al data.
  AND 


There is a 2nd assay showing low function
Do not use code with conflicting evidence.
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Strong
Modification Type: Strength
Use proband counting system described below in text.
PS4 = 4+ points
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Moderate
Modification Type: Strength
Use proband counting point system described in text below.
PS4_moderate = 2-3 points
Gene: TP53 (HGNC:11998)
Evidence Code: PS4 — Supporting
Modification Type: Strength
Use proband counting point system described in text below.
 PS4_Suppporting = 1 point
Gene: TP53 (HGNC:11998)
Evidence Code: PM1 — Moderate
Modification Type: Disease-specific,Strength
This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)
Gene: TP53 (HGNC:11998)
Evidence Code: PM2 — Supporting
Modification Type: Disease-specific,General recommendation
Variant needs to be absent from controls.
The variant must be absent from population databases. gnomAD is the preferred population database at this time (
http://gnomad.broadinstitute.org
). The most recent version of gnomAD with a non-cancer subpopulation should be used; however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.
Gene: TP53 (HGNC:11998)
Evidence Code: PM5 — Moderate
Modification Type: Strength
Multiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.
Gene: TP53 (HGNC:11998)
Evidence Code: PM5 — Supporting
Modification Type: Strength
Grantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.
Gene: TP53 (HGNC:11998)
Evidence Code: PM6 — Very Strong
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.
Gene: TP53 (HGNC:11998)
Evidence Code: PM6 — Strong
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PM6 — Moderate
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
 1 point (for 1 cancer from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PM6 — Supporting
Modification Type: Strength
Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
0.5 point (1 cancer from the moderate criteria list)
Gene: TP53 (HGNC:11998)
Evidence Code: PP1 — Strong
Modification Type: Strength
Cosegregation must be observed ≥7 meioses in >1 family in to apply this rule.
Gene: TP53 (HGNC:11998)
Evidence Code: PP1 — Moderate
Modification Type: Strength
Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule.
Gene: TP53 (HGNC:11998)
Evidence Code: PP1 — Supporting
Modification Type: Strength
Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule
Gene: TP53 (HGNC:11998)
Evidence Code: PP3 — Moderate
Modification Type: Strength
PolyPhen2 and SIFT in silico modeling programs should not be used for this gene.
Missense variants: aGVGD (Zebrafish; Class C65 required) and BayesDel (score ≥ 0.16)
Gene: TP53 (HGNC:11998)
Evidence Code: PP3 — Supporting
Modification Type: Strength
PolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:




Missense variants: aGVGD (Zebrafish; Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)


Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).
Gene: TP53 (HGNC:11998)
Evidence Code: PP4 — Supporting
Modification Type: Disease-specific
Use modified PS4 criteria instead of PP4 code
Gene: TP53 (HGNC:11998)
Evidence Code: BA1 — Stand Alone
Modification Type: Disease-specific
Frequency cutoff of 0.1% minimum of 5 alleles present in the population
Gene: TP53 (HGNC:11998)
Evidence Code: BS1 — Strong
Modification Type: Disease-specific
Frequency cutoff of 0.03%; minimum of 5 alleles present in the population.




Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.


To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.
Gene: TP53 (HGNC:11998)
Evidence Code: BS2 — Strong
Modification Type: Disease-specific
Observed in ≥8 cancer free 60+ year old females obtained from the same data source.
Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:




This evidence code can be used when a variant is observed in ≥8 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.
Gene: TP53 (HGNC:11998)
Evidence Code: BS2 — Supporting
Modification Type: Disease-specific
Observed in 2-7 cancer free 60+ year old females obtained from the same data source.
Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:




This evidence code can be used when a variant is observed in 2-7 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.
Gene: TP53 (HGNC:11998)
Evidence Code: BS3 — Strong
Modification Type: Strength
Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:




No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
OR
There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function.
Do not use code with conflicting evidence
Gene: TP53 (HGNC:11998)
Evidence Code: BS3 — Supporting
Modification Type: Strength
Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:




No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
OR


There is a 2nd assay demonstrating retained function
Do not use code with conflicting evidence.
No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:


No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
AND 
 There is a 2nd assay showing retained function
Do not use code with conflicting evidence
Gene: TP53 (HGNC:11998)
Evidence Code: BS4 — Strong
Modification Type: Disease-specific
Variant segregates to opposite side of the family who meets LFS criteria.
OR
Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.
Gene: TP53 (HGNC:11998)
Evidence Code: BP2 — Supporting
Modification Type: Disease-specific
This evidence code can be applied in either scenario below:




Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or


When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.
Gene: TP53 (HGNC:11998)
Evidence Code: BP4 — Supporting
Modification Type: Disease-specific
Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity Splicing: Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).
Gene: TP53 (HGNC:11998)
Evidence Code: BP7 — Supporting
Modification Type: Disease-specific
Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.