Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.455C>T (p.Pro152Leu)

CA000204

142766 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6bf64717-7983-4329-bddb-4b28f0690106
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.455C>T
NM_000546.5(TP53):c.455C>T (p.Pro152Leu)
NC_000017.11:g.7675157G>A
CM000679.2:g.7675157G>A
NC_000017.10:g.7578475G>A
CM000679.1:g.7578475G>A
NC_000017.9:g.7519200G>A
NG_017013.2:g.17394C>T
ENST00000503591.2:c.455C>T
ENST00000508793.6:c.455C>T
ENST00000509690.6:c.59C>T
ENST00000514944.6:c.176C>T
ENST00000604348.6:c.434C>T
ENST00000269305.9:c.455C>T
ENST00000269305.8:c.455C>T
ENST00000359597.8:c.455C>T
ENST00000413465.6:c.455C>T
ENST00000420246.6:c.455C>T
ENST00000445888.6:c.455C>T
ENST00000455263.6:c.455C>T
ENST00000504290.5:c.59C>T
ENST00000504937.5:c.59C>T
ENST00000505014.5:n.711C>T
ENST00000508793.5:c.455C>T
ENST00000509690.5:c.59C>T
ENST00000510385.5:c.59C>T
ENST00000514944.5:c.176C>T
ENST00000610292.4:c.338C>T
ENST00000610538.4:c.338C>T
ENST00000610623.4:c.-23C>T
ENST00000615910.4:c.422C>T
ENST00000617185.4:c.455C>T
ENST00000618944.4:c.-23C>T
ENST00000619186.4:c.-23C>T
ENST00000619485.4:c.338C>T
ENST00000620739.4:c.338C>T
ENST00000622645.4:c.338C>T
ENST00000635293.1:c.338C>T
NM_001126112.2:c.455C>T
NM_001126113.2:c.455C>T
NM_001126114.2:c.455C>T
NM_001126115.1:c.59C>T
NM_001126116.1:c.59C>T
NM_001126117.1:c.59C>T
NM_001126118.1:c.338C>T
NM_001276695.1:c.338C>T
NM_001276696.1:c.338C>T
NM_001276697.1:c.-23C>T
NM_001276698.1:c.-23C>T
NM_001276699.1:c.-23C>T
NM_001276760.1:c.338C>T
NM_001276761.1:c.338C>T
NM_001276695.2:c.338C>T
NM_001276696.2:c.338C>T
NM_001276697.2:c.-23C>T
NM_001276698.2:c.-23C>T
NM_001276699.2:c.-23C>T
NM_001276760.2:c.338C>T
NM_001276761.2:c.338C>T
NM_000546.6:c.455C>T
NM_001126112.3:c.455C>T
NM_001126113.3:c.455C>T
NM_001126114.3:c.455C>T
NM_001126115.2:c.59C>T
NM_001126116.2:c.59C>T
NM_001126117.2:c.59C>T
NM_001126118.2:c.338C>T
NM_001276695.3:c.338C>T
NM_001276696.3:c.338C>T
NM_001276697.3:c.-23C>T
NM_001276698.3:c.-23C>T
NM_001276699.3:c.-23C>T
NM_001276760.3:c.338C>T
NM_001276761.3:c.338C>T
More

Pathogenic

Met criteria codes 7
PP4_Moderate PM2_Supporting PM1 PP3_Moderate PS4 PS3 PP1
Not Met criteria codes 10
BA1 PM5 BS2 BS1 BS4 BS3 PVS1 BP4 PS1 PS2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.455C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 152 (p.Pro152Leu). This variant has been reported in 14 unrelated probands/families meeting Classic or Revised Chompret criteria, and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 8.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs26014290, 15654278, 10486318, 25584008, 17308077, Internal lab contributors; SCV000218779.10, SCV000187230.8). The variant has been reported to segregate with LFS-associated cancers in 4 meioses in 2 families (PP1; PMID: 10486318, Internal lab contributors SCV000187230.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors SCV000187230.8). This variant has an allele frequency of 0.000001695 (2/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).. In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 28 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (PM1, ≥ 10 somatic occurrences, PMID: 30311369). Computational predictor scores (BayesDel =0.558; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PP4_Moderate, PP1, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024).
Met criteria codes
PP4_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors SCV000187230.8).
PM2_Supporting
This variant has an allele frequency of 0.000001695 (2/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
PM1
This variant has 28 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369).
PP3_Moderate
Computational predictor scores (BayesDel =0.558; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).
PS4
PS4_VERY STRONG This variant has been reported in 14 unrelated probands/families meeting Classic or Revised Chompret criteria, and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 8.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs26014290, 15654278, 10486318, 25584008, 17308077, Internal lab contributors; SCV000218779.10, SCV000187230.8).
PS3
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965).
PP1
The variant has been reported to segregate with LFS-associated cancers in 4 meioses in 2 families (PP1; PMID: 10486318, Internal lab contributors SCV000187230.8).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
3 different missense variants (c.455C>A p.Pro152Gln, c.455C>G p.Pro152Arg, c.454C>T p.Pro152Ser) in the same codon have been reported (ClinVar Variation IDs 1058730, 824998, 482230). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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