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.332T>A (p.Leu111Gln)

CA16603051

376632 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0787d46b-7fbc-44b2-88f1-eefbc14eed32
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.332T>A
NM_000546.6(TP53):c.332T>A (p.Leu111Gln)
NC_000017.11:g.7676037A>T
CM000679.2:g.7676037A>T
NC_000017.10:g.7579355A>T
CM000679.1:g.7579355A>T
NC_000017.9:g.7520080A>T
NG_017013.2:g.16514T>A
ENST00000503591.2:c.332T>A
ENST00000508793.6:c.332T>A
ENST00000509690.6:c.-21-801T>A
ENST00000514944.6:c.96+345T>A
ENST00000604348.6:c.332T>A
ENST00000269305.9:c.332T>A
ENST00000269305.8:c.332T>A
ENST00000359597.8:c.332T>A
ENST00000413465.6:c.332T>A
ENST00000420246.6:c.332T>A
ENST00000445888.6:c.332T>A
ENST00000455263.6:c.332T>A
ENST00000503591.1:c.332T>A
ENST00000505014.5:n.588T>A
ENST00000508793.5:c.332T>A
ENST00000509690.5:c.-21-801T>A
ENST00000514944.5:c.96+345T>A
ENST00000604348.5:c.332T>A
ENST00000610292.4:c.215T>A
ENST00000610538.4:c.215T>A
ENST00000615910.4:c.332T>A
ENST00000617185.4:c.332T>A
ENST00000619485.4:c.215T>A
ENST00000620739.4:c.215T>A
ENST00000622645.4:c.215T>A
ENST00000635293.1:c.215T>A
NM_000546.5:c.332T>A
NM_001126112.2:c.332T>A
NM_001126113.2:c.332T>A
NM_001126114.2:c.332T>A
NM_001126118.1:c.215T>A
NM_001276695.1:c.215T>A
NM_001276696.1:c.215T>A
NM_001276760.1:c.215T>A
NM_001276761.1:c.215T>A
NM_001276695.2:c.215T>A
NM_001276696.2:c.215T>A
NM_001276760.2:c.215T>A
NM_001276761.2:c.215T>A
NM_001126112.3:c.332T>A
NM_001126113.3:c.332T>A
NM_001126114.3:c.332T>A
NM_001126118.2:c.215T>A
NM_001276695.3:c.215T>A
NM_001276696.3:c.215T>A
NM_001276760.3:c.215T>A
NM_001276761.3:c.215T>A
More

Pathogenic

Met criteria codes 6
PM2_Supporting PP4_Moderate PP3_Moderate PM1_Supporting PS4_Supporting PS3
Not Met criteria codes 12
PP1 PM5 BS2 BS4 BS3 BS1 BP4 BP7 PS1 PS2 BA1 PVS1

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.332T>A variant in TP53 is a missense variant predicted to cause substitution of leucine by glutamine at amino acid 111 (p.Leu111Gln). This variant has been reported in2 unrelated probands 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 contributors). 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). Computational predictor scores (BayesDel = 0.36783; Align GVGD = Class C65) 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). This variant has 4 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). 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 contributor). 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: PS3, PS4_Supporting, PP3_Moderate, PM1_Supporting, PM2_Supporting, PP4_Moderate: Bayesian Points: 11; VCEP specifications version 2.3.
Met criteria codes
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 contributor).
PP3_Moderate
Computational predictor scores (BayesDel = 0.36783; Align GVGD = Class C65) 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).
PM1_Supporting
This variant has 4 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).
PS4_Supporting
This variant has been reported in2 unrelated probands 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 contributors).
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).
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
4 different missense variants (p.Leu111Arg, p.Leu111Pro, p.Leu111Val, p.Leu111Met) in the same codon have been reported (ClinVar Variation IDs: 376631, 376630, 1730178, 836750). However, these variants do not meet criteria for PM5 code application (PM5 not met).
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
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
PS1
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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