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.833C>A (p.Pro278His)

CA16603063

376646 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 472a5af5-21c5-49fe-89db-478d17dcd62d
Approved on: 2026-06-04
Published on: 2026-09-22

HGVS expressions

NM_000546.6(TP53):c.833C>A (p.Pro278His)
NM_000546.6:c.833C>A
NC_000017.11:g.7673787G>T
CM000679.2:g.7673787G>T
NC_000017.10:g.7577105G>T
CM000679.1:g.7577105G>T
NC_000017.9:g.7517830G>T
NG_017013.2:g.18764C>A
ENST00000503591.2:c.833C>A
ENST00000508793.6:c.833C>A
ENST00000509690.6:c.437C>A
ENST00000514944.6:c.554C>A
ENST00000604348.6:c.812C>A
ENST00000269305.9:c.833C>A
ENST00000269305.8:c.833C>A
ENST00000359597.8:c.833C>A
ENST00000413465.6:c.782+394C>A
ENST00000420246.6:c.833C>A
ENST00000445888.6:c.833C>A
ENST00000455263.6:c.833C>A
ENST00000504290.5:c.437C>A
ENST00000504937.5:c.437C>A
ENST00000509690.5:c.437C>A
ENST00000510385.5:c.437C>A
ENST00000610292.4:c.716C>A
ENST00000610538.4:c.716C>A
ENST00000610623.4:c.356C>A
ENST00000615910.4:c.800C>A
ENST00000617185.4:c.833C>A
ENST00000618944.4:c.356C>A
ENST00000619186.4:c.356C>A
ENST00000619485.4:c.716C>A
ENST00000620739.4:c.716C>A
ENST00000622645.4:c.716C>A
ENST00000635293.1:c.716C>A
NM_000546.5:c.833C>A
NM_001126112.2:c.833C>A
NM_001126113.2:c.833C>A
NM_001126114.2:c.833C>A
NM_001126115.1:c.437C>A
NM_001126116.1:c.437C>A
NM_001126117.1:c.437C>A
NM_001126118.1:c.716C>A
NM_001276695.1:c.716C>A
NM_001276696.1:c.716C>A
NM_001276697.1:c.356C>A
NM_001276698.1:c.356C>A
NM_001276699.1:c.356C>A
NM_001276760.1:c.716C>A
NM_001276761.1:c.716C>A
NM_001276695.2:c.716C>A
NM_001276696.2:c.716C>A
NM_001276697.2:c.356C>A
NM_001276698.2:c.356C>A
NM_001276699.2:c.356C>A
NM_001276760.2:c.716C>A
NM_001276761.2:c.716C>A
NM_001126112.3:c.833C>A
NM_001126113.3:c.833C>A
NM_001126114.3:c.833C>A
NM_001126115.2:c.437C>A
NM_001126116.2:c.437C>A
NM_001126117.2:c.437C>A
NM_001126118.2:c.716C>A
NM_001276695.3:c.716C>A
NM_001276696.3:c.716C>A
NM_001276697.3:c.356C>A
NM_001276698.3:c.356C>A
NM_001276699.3:c.356C>A
NM_001276760.3:c.716C>A
NM_001276761.3:c.716C>A
More

Pathogenic

Met criteria codes 5
PP4_Moderate PM2_Supporting PM1_Supporting PP3_Moderate PS3
Not Met criteria codes 12
PVS1 BS4 BS3 BS1 BS2 BP7 BP4 PS2 PS4 PS1 BA1 PP1

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.833C>A variant in TP53 is a missense variant predicted to cause substitution of proline by histidine at amino acid 278 (p.Pro278His). 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). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). 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 = 0.6078; 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). 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 Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP, however, please note that this variant has not been reported in a clinical case to our knowledge: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1_Supporting. (Bayesian Points: 10; 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).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
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_Moderate
Computational predictor scores (BayesDel = 0.6078; 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).
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
PVS1
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
BS2
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
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
PS4
To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met).
PS1
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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