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_000546.5(TP53):c.353C>T (p.Thr118Ile)

CA16620635

419837 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: fc7cc0ba-f84e-46c8-acb3-ef170d24b394
Approved on: 2025-03-04
Published on: 2025-06-23

HGVS expressions

NM_000546.5:c.353C>T
NM_000546.5(TP53):c.353C>T (p.Thr118Ile)
NC_000017.11:g.7676016G>A
CM000679.2:g.7676016G>A
NC_000017.10:g.7579334G>A
CM000679.1:g.7579334G>A
NC_000017.9:g.7520059G>A
NG_017013.2:g.16535C>T
ENST00000503591.2:c.353C>T
ENST00000508793.6:c.353C>T
ENST00000509690.6:c.-21-780C>T
ENST00000514944.6:c.96+366C>T
ENST00000604348.6:c.353C>T
ENST00000269305.9:c.353C>T
ENST00000269305.8:c.353C>T
ENST00000359597.8:c.353C>T
ENST00000413465.6:c.353C>T
ENST00000420246.6:c.353C>T
ENST00000445888.6:c.353C>T
ENST00000455263.6:c.353C>T
ENST00000503591.1:c.353C>T
ENST00000505014.5:n.609C>T
ENST00000508793.5:c.353C>T
ENST00000509690.5:c.-21-780C>T
ENST00000514944.5:c.96+366C>T
ENST00000604348.5:c.353C>T
ENST00000610292.4:c.236C>T
ENST00000610538.4:c.236C>T
ENST00000615910.4:c.340+9C>T
ENST00000617185.4:c.353C>T
ENST00000619485.4:c.236C>T
ENST00000620739.4:c.236C>T
ENST00000622645.4:c.236C>T
ENST00000635293.1:c.236C>T
NM_001126112.2:c.353C>T
NM_001126113.2:c.353C>T
NM_001126114.2:c.353C>T
NM_001126118.1:c.236C>T
NM_001276695.1:c.236C>T
NM_001276696.1:c.236C>T
NM_001276760.1:c.236C>T
NM_001276761.1:c.236C>T
NM_001276695.2:c.236C>T
NM_001276696.2:c.236C>T
NM_001276760.2:c.236C>T
NM_001276761.2:c.236C>T
NM_000546.6:c.353C>T
NM_001126112.3:c.353C>T
NM_001126113.3:c.353C>T
NM_001126114.3:c.353C>T
NM_001126118.2:c.236C>T
NM_001276695.3:c.236C>T
NM_001276696.3:c.236C>T
NM_001276760.3:c.236C>T
NM_001276761.3:c.236C>T
More

Likely Benign

Met criteria codes 4
BS3 BS2_Supporting PP3_Moderate PM2_Supporting
Not Met criteria codes 11
BS4 BS1 BP2 BP4 PS2 PS3 PS1 PP1 PM6 PM1 BA1

Evidence Links 3

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.353C>T variant in TP53 is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 118 (p.Thr118Ile). 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; ClinVar SCVs: SCV000664386.6). This variant has an allele frequency of 0.0000006203 (1/1612196 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.3466; 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 likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3_Moderate. (Bayesian Points: -2; VCEP specifications version 2.3).
Met criteria codes
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 29979965, 30224644).
noLOF PubMed:29979965
noLOF/noDNE PubMed:30224644
Functional PubMed:12826609
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; ClinVar SCVs: SCV000664386.6).
PP3_Moderate
Computational predictor scores (BayesDel = 0.3466; 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 0.0000006203 (1/1612196 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).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Absent in gnomAD v2.1.1 (non-cancer)
BP2
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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).
BA1
Absent in gnomAD v2.1.1 (non-cancer)
Curation History
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