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.337T>A (p.Phe113Ile)

CA397844510

1469551 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 454d1e83-d15f-4d8a-b020-b002fddfb132
Approved on: 2026-08-06
Published on: 2026-09-22

HGVS expressions

NM_000546.6(TP53):c.337T>A (p.Phe113Ile)
NM_000546.6:c.337T>A
NC_000017.11:g.7676032A>T
CM000679.2:g.7676032A>T
NC_000017.10:g.7579350A>T
CM000679.1:g.7579350A>T
NC_000017.9:g.7520075A>T
NG_017013.2:g.16519T>A
ENST00000503591.2:c.337T>A
ENST00000508793.6:c.337T>A
ENST00000509690.6:c.-21-796T>A
ENST00000514944.6:c.96+350T>A
ENST00000604348.6:c.337T>A
ENST00000269305.9:c.337T>A
ENST00000269305.8:c.337T>A
ENST00000359597.8:c.337T>A
ENST00000413465.6:c.337T>A
ENST00000420246.6:c.337T>A
ENST00000445888.6:c.337T>A
ENST00000455263.6:c.337T>A
ENST00000503591.1:c.337T>A
ENST00000505014.5:n.593T>A
ENST00000508793.5:c.337T>A
ENST00000509690.5:c.-21-796T>A
ENST00000514944.5:c.96+350T>A
ENST00000604348.5:c.337T>A
ENST00000610292.4:c.220T>A
ENST00000610538.4:c.220T>A
ENST00000615910.4:c.334-1T>A
ENST00000617185.4:c.337T>A
ENST00000619485.4:c.220T>A
ENST00000620739.4:c.220T>A
ENST00000622645.4:c.220T>A
ENST00000635293.1:c.220T>A
NM_000546.5:c.337T>A
NM_001126112.2:c.337T>A
NM_001126113.2:c.337T>A
NM_001126114.2:c.337T>A
NM_001126118.1:c.220T>A
NM_001276695.1:c.220T>A
NM_001276696.1:c.220T>A
NM_001276760.1:c.220T>A
NM_001276761.1:c.220T>A
NM_001276695.2:c.220T>A
NM_001276696.2:c.220T>A
NM_001276760.2:c.220T>A
NM_001276761.2:c.220T>A
NM_001126112.3:c.337T>A
NM_001126113.3:c.337T>A
NM_001126114.3:c.337T>A
NM_001126118.2:c.220T>A
NM_001276695.3:c.220T>A
NM_001276696.3:c.220T>A
NM_001276760.3:c.220T>A
NM_001276761.3:c.220T>A
More

Likely Pathogenic

Met criteria codes 4
BS2_Supporting PM2_Supporting PP4_Moderate PS3
Not Met criteria codes 13
BA1 BP5 BP4 BS4 BS3 BS1 PP1 PP3 PM1 PM5 PS2 PS4 PS1

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 2.4

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.337T>A variant in TP53 is a missense variant predicted to cause substitution of phenylalanine by isoleucine at amino acid 113 (p.Phe113Ile). 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). This variant received a total of 0.5 points in one proband (PS4 not met; Internal lab contributor). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_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 by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325). 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: PM2_Supporting, PS3, PP4_Moderate, BS2_Supporting. (Bayesian Points: 6; VCEP specifications version 2.4)
Met criteria codes
BS2_Supporting
This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
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).
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).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
PM5
Six different missense variants affecting the same codon have been reported (c.337T>C, p.Phe113Leu; c.337T>G, p.Phe113Val; c.338T>C, p.Phe113Ser; c.338T>G, p.Phe113Cys; c.339C>A, p.Phe113Leu; c.339C>G, p.Phe113Leu) (ClinVar Variation IDs: 3634432, 141302, 823709, 634690, 2125367, 2702402). However, these variants do not meet the criteria for PM5 code application as the Grantham scores are all higher than this variant (PM5 not met).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant received a total of 0.5 points in one proband (PS4 not met; Internal lab contributor).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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