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_001126112.2(TP53):c.380C>A (p.Ser127Tyr)

CA397843908

656751 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 69da5ddc-e144-48e0-aa76-30754f54757b
Approved on: 2026-01-06
Published on: 2026-01-14

HGVS expressions

NM_001126112.2:c.380C>A
NM_001126112.2(TP53):c.380C>A (p.Ser127Tyr)
NC_000017.11:g.7675232G>T
CM000679.2:g.7675232G>T
NC_000017.10:g.7578550G>T
CM000679.1:g.7578550G>T
NC_000017.9:g.7519275G>T
NG_017013.2:g.17319C>A
ENST00000503591.2:c.380C>A
ENST00000508793.6:c.380C>A
ENST00000509690.6:c.-17C>A
ENST00000514944.6:c.101C>A
ENST00000604348.6:c.376-17C>A
ENST00000269305.9:c.380C>A
ENST00000269305.8:c.380C>A
ENST00000359597.8:c.380C>A
ENST00000413465.6:c.380C>A
ENST00000420246.6:c.380C>A
ENST00000445888.6:c.380C>A
ENST00000455263.6:c.380C>A
ENST00000503591.1:c.380C>A
ENST00000504290.5:c.-17C>A
ENST00000504937.5:c.-17C>A
ENST00000505014.5:n.636C>A
ENST00000508793.5:c.380C>A
ENST00000509690.5:c.-17C>A
ENST00000510385.5:c.-17C>A
ENST00000514944.5:c.101C>A
ENST00000604348.5:c.376-17C>A
ENST00000610292.4:c.263C>A
ENST00000610538.4:c.263C>A
ENST00000610623.4:c.-98C>A
ENST00000615910.4:c.347C>A
ENST00000617185.4:c.380C>A
ENST00000618944.4:c.-98C>A
ENST00000619186.4:c.-98C>A
ENST00000619485.4:c.263C>A
ENST00000620739.4:c.263C>A
ENST00000622645.4:c.263C>A
ENST00000635293.1:c.263C>A
NM_000546.5:c.380C>A
NM_001126113.2:c.380C>A
NM_001126114.2:c.380C>A
NM_001126115.1:c.-17C>A
NM_001126116.1:c.-17C>A
NM_001126117.1:c.-17C>A
NM_001126118.1:c.263C>A
NM_001276695.1:c.263C>A
NM_001276696.1:c.263C>A
NM_001276697.1:c.-98C>A
NM_001276698.1:c.-98C>A
NM_001276699.1:c.-98C>A
NM_001276760.1:c.263C>A
NM_001276761.1:c.263C>A
NM_001276695.2:c.263C>A
NM_001276696.2:c.263C>A
NM_001276697.2:c.-98C>A
NM_001276698.2:c.-98C>A
NM_001276699.2:c.-98C>A
NM_001276760.2:c.263C>A
NM_001276761.2:c.263C>A
NM_000546.6:c.380C>A
NM_001126112.3:c.380C>A
NM_001126113.3:c.380C>A
NM_001126114.3:c.380C>A
NM_001126115.2:c.-17C>A
NM_001126116.2:c.-17C>A
NM_001126117.2:c.-17C>A
NM_001126118.2:c.263C>A
NM_001276695.3:c.263C>A
NM_001276696.3:c.263C>A
NM_001276697.3:c.-98C>A
NM_001276698.3:c.-98C>A
NM_001276699.3:c.-98C>A
NM_001276760.3:c.263C>A
NM_001276761.3:c.263C>A
More

Pathogenic

Met criteria codes 7
PP4_Moderate PS3 PS2_Moderate PM1 PP3_Moderate PS4_Supporting PM2_Supporting
Not Met criteria codes 8
PS1 PP1 PM5 BS4 BS3 BS1 BS2 BP4

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 2.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.380C>A variant in TP53 is a missense variant predicted to cause substitution of Serine by Tyrosine at amino acid 127 (p.Ser127Tyr). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor). This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors). 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 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 = 0.6001; 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 10 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 Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PS4_Supporting, PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1 (Bayesian Points: 14; VCEP specifications version 2.4)
Met criteria codes
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).
PS2_Moderate
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor).
PM1
This variant has 10 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).
PP3_Moderate
Computational predictor scores (BayesDel = 0.6001; 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).
PS4_Supporting
This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
PM5
Three different missense variants (p.Ser127Cys, p.Ser127Pro, p.Ser127Thr) in the same codon have been reported (ClinVar Variation IDs: 219532, 934410, 824232). p.Ser127Cys and p.Ser127Thr would be classified as at least Likely Pathogenic by VCEP Specifications, however, this code is not needed for Pathogenic classification of this variant. (PM5 not evaluated).
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
BS2
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
Curation History
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