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.1010G>T (p.Arg337Leu)

CA000015

142828 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9b60fc0c-b12b-4417-b0a6-bdf7f14ce777
Approved on: 2025-05-07
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.1010G>T
NM_000546.6(TP53):c.1010G>T (p.Arg337Leu)
NC_000017.11:g.7670699C>A
CM000679.2:g.7670699C>A
NC_000017.10:g.7574017C>A
CM000679.1:g.7574017C>A
NC_000017.9:g.7514742C>A
NG_017013.2:g.21852G>T
ENST00000503591.2:c.1010G>T
ENST00000508793.6:c.1010G>T
ENST00000509690.6:c.614G>T
ENST00000514944.6:c.731G>T
ENST00000604348.6:c.989G>T
ENST00000269305.9:c.1010G>T
ENST00000269305.8:c.1010G>T
ENST00000359597.8:c.993+2836G>T
ENST00000413465.6:c.782+3482G>T
ENST00000420246.6:c.*117G>T
ENST00000445888.6:c.1010G>T
ENST00000455263.6:c.*29G>T
ENST00000504290.5:c.*29G>T
ENST00000504937.5:c.614G>T
ENST00000510385.5:c.*117G>T
ENST00000576024.1:c.54-1009G>T
ENST00000610292.4:c.893G>T
ENST00000610538.4:c.*29G>T
ENST00000610623.4:c.*29G>T
ENST00000615910.4:c.977G>T
ENST00000617185.4:c.*117G>T
ENST00000618944.4:c.*117G>T
ENST00000619186.4:c.533G>T
ENST00000619485.4:c.893G>T
ENST00000620739.4:c.893G>T
ENST00000622645.4:c.*117G>T
ENST00000635293.1:c.893G>T
NM_000546.5:c.1010G>T
NM_001126112.2:c.1010G>T
NM_001126113.2:c.*29G>T
NM_001126114.2:c.*117G>T
NM_001126115.1:c.614G>T
NM_001126116.1:c.*117G>T
NM_001126117.1:c.*29G>T
NM_001126118.1:c.893G>T
NM_001276695.1:c.*29G>T
NM_001276696.1:c.*117G>T
NM_001276697.1:c.533G>T
NM_001276698.1:c.*117G>T
NM_001276699.1:c.*29G>T
NM_001276760.1:c.893G>T
NM_001276761.1:c.893G>T
NM_001276695.2:c.*29G>T
NM_001276696.2:c.*117G>T
NM_001276697.2:c.533G>T
NM_001276698.2:c.*117G>T
NM_001276699.2:c.*29G>T
NM_001276760.2:c.893G>T
NM_001276761.2:c.893G>T
NM_001126112.3:c.1010G>T
NM_001126113.3:c.*29G>T
NM_001126114.3:c.*117G>T
NM_001126115.2:c.614G>T
NM_001126116.2:c.*117G>T
NM_001126117.2:c.*29G>T
NM_001126118.2:c.893G>T
NM_001276695.3:c.*29G>T
NM_001276696.3:c.*117G>T
NM_001276697.3:c.533G>T
NM_001276698.3:c.*117G>T
NM_001276699.3:c.*29G>T
NM_001276760.3:c.893G>T
NM_001276761.3:c.893G>T
More

Likely Pathogenic

Met criteria codes 5
PS4_Supporting PM2_Supporting BP4 PS3 PM1
Not Met criteria codes 8
BS4 BS3 BS2 BA1 PP1 PP3 PP4 PM5

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(TP53):c.1010G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 337 (p.Arg337Leu). This variant has been reported in 2 families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributor). This variant is absent from gnomAD v4.1.0 (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 = 0.067; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). This variant has 20 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) (PM1). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, BP4, PM2_Supporting, PS4_Supporting. (Bayesian Points: 7; VCEP specifications version 2.3)
Met criteria codes
PS4_Supporting
This variant has been reported in 2 families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributor).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BP4
Computational predictor scores (BayesDel = 0.067; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4).
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).
PM1
This variant has 20 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) (PM1).
Not Met criteria codes
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
BS2
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
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
PM5
Although other missense variants in the same codon have been reported, these variants do not meet criteria for PM5 code application (PM5 not met).
Curation History
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