Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000546.6(TP53):c.337T>G (p.Phe113Val)

CA000124

141302 (ClinVar)

Gene: TP53 (HGNC:7157)

Condition: Li-Fraumeni syndrome (MONDO:0018875)

Inheritance Mode: Autosomal dominant inheritance

UUID: bc642d79-0efb-4f57-9ae3-177a7515c323

Approved on: 2026-07-01

Published on: 2026-09-22

HGVS expressions

NM_000546.6:c.337T>G

NM_000546.6(TP53):c.337T>G (p.Phe113Val)

NC_000017.11:g.7676032A>C

CM000679.2:g.7676032A>C

NC_000017.10:g.7579350A>C

CM000679.1:g.7579350A>C

NC_000017.9:g.7520075A>C

NG_017013.2:g.16519T>G

ENST00000503591.2:c.337T>G

ENST00000508793.6:c.337T>G

ENST00000509690.6:c.-21-796T>G

ENST00000514944.6:c.96+350T>G

ENST00000604348.6:c.337T>G

ENST00000269305.9:c.337T>G

ENST00000269305.8:c.337T>G

ENST00000359597.8:c.337T>G

ENST00000413465.6:c.337T>G

ENST00000420246.6:c.337T>G

ENST00000445888.6:c.337T>G

ENST00000455263.6:c.337T>G

ENST00000503591.1:c.337T>G

ENST00000505014.5:n.593T>G

ENST00000508793.5:c.337T>G

ENST00000509690.5:c.-21-796T>G

ENST00000514944.5:c.96+350T>G

ENST00000604348.5:c.337T>G

ENST00000610292.4:c.220T>G

ENST00000610538.4:c.220T>G

ENST00000615910.4:c.334-1T>G

ENST00000617185.4:c.337T>G

ENST00000619485.4:c.220T>G

ENST00000620739.4:c.220T>G

ENST00000622645.4:c.220T>G

ENST00000635293.1:c.220T>G

NM_000546.5:c.337T>G

NM_001126112.2:c.337T>G

NM_001126113.2:c.337T>G

NM_001126114.2:c.337T>G

NM_001126118.1:c.220T>G

NM_001276695.1:c.220T>G

NM_001276696.1:c.220T>G

NM_001276760.1:c.220T>G

NM_001276761.1:c.220T>G

NM_001276695.2:c.220T>G

NM_001276696.2:c.220T>G

NM_001276760.2:c.220T>G

NM_001276761.2:c.220T>G

NM_001126112.3:c.337T>G

NM_001126113.3:c.337T>G

NM_001126114.3:c.337T>G

NM_001126118.2:c.220T>G

NM_001276695.3:c.220T>G

NM_001276696.3:c.220T>G

NM_001276760.3:c.220T>G

NM_001276761.3:c.220T>G

Likely Pathogenic

PS3 PM1_Supporting PP3 PP4_Moderate PM2_Supporting

PS2 PS4 PS1 BP4 PP1 PM6 PM5 BA1 BS2 BS4 BS1

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.337T>G variant in TP53 is a missense variant predicted to cause substitution of phenylalanine by valine at amino acid 113 (p.Phe113Val). 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, ClinVar SCV000754598.8, SCV000184579.8). This variant received a total of 0.5 points across 1 proband. (PS4 not met; 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 by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325). Computational predictor scores (BayesDel =0.3138; Align GVGD = Class C45) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 6 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). 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: PP4_Moderate, BS2_Moderate, PM2_Supporting, PS3, PP3, PM1_Supporting (Bayesian Points: 7; VCEP specifications version 2.4).

PS3

In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325).

PM1_Supporting

This variant has 6 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).

PP3

Computational predictor scores (BayesDel =0.3138; Align GVGD = Class C45) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).

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, ClinVar SCV000754598.8, SCV000184579.8).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS2

GeneDx case of female with breast in 20s and VAF of 35% is highly suspicious for constitutional mosaicism, but as fibroblasts are negative PS2 was not counted. The VCEP feels this case evidence is supportive of the LP classification of this variant as appropriate, even if clinical codes are not actually applied.

PS4

This variant received a total of 0.5 points across 1 proband. (PS4 not met; Internal lab contributor).

PS1