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 computed assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.761T>A (p.Ile254Asn)

CA397837760

856299 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: fa49eea4-1941-461d-b4ed-44fa217fb4cc
Approved on: 2025-12-05
Published on: 2025-12-05

HGVS expressions

NM_000546.6(TP53):c.761T>A (p.Ile254Asn)
NM_000546.6:c.761T>A
NC_000017.11:g.7674202A>T
CM000679.2:g.7674202A>T
NC_000017.10:g.7577520A>T
CM000679.1:g.7577520A>T
NC_000017.9:g.7518245A>T
NG_017013.2:g.18349T>A
ENST00000503591.2:c.761T>A
ENST00000508793.6:c.761T>A
ENST00000509690.6:c.365T>A
ENST00000514944.6:c.482T>A
ENST00000604348.6:c.740T>A
ENST00000269305.9:c.761T>A
ENST00000269305.8:c.761T>A
ENST00000359597.8:c.761T>A
ENST00000413465.6:c.761T>A
ENST00000420246.6:c.761T>A
ENST00000445888.6:c.761T>A
ENST00000455263.6:c.761T>A
ENST00000504290.5:c.365T>A
ENST00000504937.5:c.365T>A
ENST00000509690.5:c.365T>A
ENST00000510385.5:c.365T>A
ENST00000610292.4:c.644T>A
ENST00000610538.4:c.644T>A
ENST00000610623.4:c.284T>A
ENST00000615910.4:c.728T>A
ENST00000617185.4:c.761T>A
ENST00000618944.4:c.284T>A
ENST00000619186.4:c.284T>A
ENST00000619485.4:c.644T>A
ENST00000620739.4:c.644T>A
ENST00000622645.4:c.644T>A
ENST00000635293.1:c.644T>A
NM_000546.5:c.761T>A
NM_001126112.2:c.761T>A
NM_001126113.2:c.761T>A
NM_001126114.2:c.761T>A
NM_001126115.1:c.365T>A
NM_001126116.1:c.365T>A
NM_001126117.1:c.365T>A
NM_001126118.1:c.644T>A
NM_001276695.1:c.644T>A
NM_001276696.1:c.644T>A
NM_001276697.1:c.284T>A
NM_001276698.1:c.284T>A
NM_001276699.1:c.284T>A
NM_001276760.1:c.644T>A
NM_001276761.1:c.644T>A
NM_001276695.2:c.644T>A
NM_001276696.2:c.644T>A
NM_001276697.2:c.284T>A
NM_001276698.2:c.284T>A
NM_001276699.2:c.284T>A
NM_001276760.2:c.644T>A
NM_001276761.2:c.644T>A
NM_001126112.3:c.761T>A
NM_001126113.3:c.761T>A
NM_001126114.3:c.761T>A
NM_001126115.2:c.365T>A
NM_001126116.2:c.365T>A
NM_001126117.2:c.365T>A
NM_001126118.2:c.644T>A
NM_001276695.3:c.644T>A
NM_001276696.3:c.644T>A
NM_001276697.3:c.284T>A
NM_001276698.3:c.284T>A
NM_001276699.3:c.284T>A
NM_001276760.3:c.644T>A
NM_001276761.3:c.644T>A
More

Pathogenic

Met criteria codes 4
PP3_Moderate PM2_Supporting PS2 PS3
Not Met criteria codes 14
PVS1 BA1 BP4 BP7 BS2 BS4 BS3 BS1 PP4 PP1 PS4 PS1 PM5 PM1

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 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.761T>A variant in TP53 is a missense variant predicted to cause substitution of isoleucine by asparagine at amino acid 254 (p.Ile254Asn). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 4 phenotype points (PS2; PMID 29070607). This variant has an allele frequency of 6.200e-7 (1/1612836 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (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). Computational predictor scores (BayesDel = 0.5449; Align GVGD = Class 65) 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: PS2, PM2_Supporting, PS3, PP3_Moderate. (Bayesian Points: 11; VCEP specifications version 2.3).
Met criteria codes
PP3_Moderate
Computational predictor scores (BayesDel = 0.5449; Align GVGD = Class 65) 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).
PM2_Supporting
This variant has an allele frequency of 6.200e-7 (1/1612836 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting).
PS2
This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 4 phenotype points (PS2; PMID 29070607).
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).
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
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
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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