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Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

TP53 VCEP ACMG/AMP Specifications

Benign
Pathogenic
Stand Alone
Strong
Supporting
Supporting
Moderate
Strong
Very Strong
Population Data

Allele frequency is greater than expected for disorder
•Comments:
••Frequency cutoff of 0.1% minimum of 5 alleles present in the population BA1

Allele frequency is greater than expected for the disorder
•Comments:
••Frequency cutoff of 0.03%; minimum of 5 alleles present in the population BS1

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
•Comments:
••Observed in >8 cancer free 60+ year old females BS2

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
•Comments:
••Observed in 2-7 cancer free 60+ year old females BS2-Supporting

Absent in population databases
•Comments:
••Variant needs to be absent from controls. PM2-Supporting

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
•Comments:
••Use proband counting point system described in the guideline..
••PS4_Suppporting = 1 point PS4-Supporting

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
•Comments:
••Use proband counting point system described in the guideline.
••PS4_moderate = 2-3 points PS4-Moderate

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
•Comments:
••Use proband counting point system described in the guideline.
••PS4 = 4+ points PS4

Computational And Predictive Data

Multiple lines of computational evidence suggest no impact on gene/gene product
•Comments:
••Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity
••Splicing: MaxEntScan and HSF BP4

A synonymous (silent) 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.
•Comments:
••Concordance of MaxEntScan and HSF; If a new alternate site is predicted, compare strength to native site in interpretation. BP7

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
•Comments:
••Grantham or BLOSUM should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. This rule cannot be used for hot spots. PM5-Supporting

Multiple lines of computational evidence support a deleterious effect on the gene or gene product
•Comments:
••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 C15 and higher are considered evidence of pathogenicity) and BayesDel (scores > 0.16 are considered evidence of pathogenic)
•••Splicing variants: MaxEntScan and HSF PP3

Multiple lines of computational evidence support a deleterious effect on the gene or gene product
•Comments:
••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) PP3-Moderate

Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
•Comments:
••This rule should not be used at this time due to limited data. PM4

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
•Comments:
••Multiple pathogenic variants (>2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham or BLOSUM should be used to compare the variants. New variant 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. PM5

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
•Comments:
••Must confirm there is no difference in splicing using in silico modeling data. PS1-Moderate

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
•Comments:
••Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. PS1

Null variant in a gene where LOF is a known mechanism of disease
•Comments:
••Defer to SVI recommendations PVS1

Functional Data

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
•Comments:
••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. BS3

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
•Comments:
••Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <e;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. BS3-Supporting

Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
•Comments:
••This rule should not be used due to the high frequency of benign missense variants. PP2

Well-established in vitro or in vivo, functional studies supportive of a damaging effect on the gene or gene product
•Comments:
••A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <e;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 PS3-Moderate

Located in a mutational hot spot and/or critical and well-established functional domain without benign variation
•Comments:
••This rule can be applied to variants in hot spots (codons 175, 248, 273, 248, 245, 282, 249), but not to variants within functional domains. Use transcript NM_000546.4.
••Also use rule for variants with >10 somatic observations cancerhotspots.org (v2) PM1

Well-established in vitro or in vivo, functional studies supportive of a damaging effect on the gene or gene product
•Comments:
••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) PS3

Segregation Data

Lack of segregation in affected members of a family
•Comments:
••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 3 should be female) above 55 years of age. BS4

Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
•Comments:
••Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule. PP1

Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
•Comments:
••Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule. PP1-Moderate

Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
•Comments:
••Cosegregation must be observed >7 meioses in >1 family in to apply this rule. PP1-Strong

De novo Data

De novo, proven
•Comments:
••Use SVI point system table.
••See Cancer Criteria List & TP53 Point Table in the guideline.
••0.5 point (1 cancer from the moderate criteria list) PS2-Supporting

De novo, assumed
•Comments:
••Use SVI point system table.
••See Cancer Criteria List & TP53 Point Table in the guideline.
••0.5 point (1 cancer from the moderate criteria list) PM6-Supporting

De novo, assumed
•Comments:
••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) PM6

De novo, proven
•Comments:
••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) PS2-Moderate

De novo, assumed
•Comments:
••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) PM6-Strong

De novo, proven
•Comments:
••Use SVI point system table.
••See Cancer Criteria List & TP53 Point Table provided in the guideline.
••2-3 points (ex. — 1 cancer from the strong criteria list or 2 from the moderate criteria list) PS2

De novo, assumed
•Comments:
••Use SVI point system table.
••See Cancer Criteria List & TP53 Point Table provided in the guideline
••>4 points (ex. — 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. PM6-Very Strong

De novo, proven
•Comments:
••Use SVI point system table.
••See Cancer Criteria List & TP53 Point Table provided in the guideline
••>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." PS2-Very Strong

Allelic Data

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
•Comments:
••Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR
••3 or more observations when phase is unknown with at least two different pathogenic/likely pathogenic TP53 variants BP2

Other Data

Patient’s phenotype and/or family history is highly specific for a disease with a single genetic etiology
•Comments:
••Use modified PS4 criteria instead of PP4 code PP4

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