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.840A>T (p.Arg280Ser)

CA397836831

988616 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 54ad9d59-0134-41c7-92ef-3b86fb2181d5
Approved on: 2026-04-02
Published on: 2026-04-22

HGVS expressions

NM_000546.6:c.840A>T
NM_000546.6(TP53):c.840A>T (p.Arg280Ser)
NC_000017.11:g.7673780T>A
CM000679.2:g.7673780T>A
NC_000017.10:g.7577098T>A
CM000679.1:g.7577098T>A
NC_000017.9:g.7517823T>A
NG_017013.2:g.18771A>T
ENST00000503591.2:c.840A>T
ENST00000508793.6:c.840A>T
ENST00000509690.6:c.444A>T
ENST00000514944.6:c.561A>T
ENST00000604348.6:c.819A>T
ENST00000269305.9:c.840A>T
ENST00000269305.8:c.840A>T
ENST00000359597.8:c.840A>T
ENST00000413465.6:c.782+401A>T
ENST00000420246.6:c.840A>T
ENST00000445888.6:c.840A>T
ENST00000455263.6:c.840A>T
ENST00000504290.5:c.444A>T
ENST00000504937.5:c.444A>T
ENST00000509690.5:c.444A>T
ENST00000510385.5:c.444A>T
ENST00000610292.4:c.723A>T
ENST00000610538.4:c.723A>T
ENST00000610623.4:c.363A>T
ENST00000615910.4:c.807A>T
ENST00000617185.4:c.840A>T
ENST00000618944.4:c.363A>T
ENST00000619186.4:c.363A>T
ENST00000619485.4:c.723A>T
ENST00000620739.4:c.723A>T
ENST00000622645.4:c.723A>T
ENST00000635293.1:c.723A>T
NM_000546.5:c.840A>T
NM_001126112.2:c.840A>T
NM_001126113.2:c.840A>T
NM_001126114.2:c.840A>T
NM_001126115.1:c.444A>T
NM_001126116.1:c.444A>T
NM_001126117.1:c.444A>T
NM_001126118.1:c.723A>T
NM_001276695.1:c.723A>T
NM_001276696.1:c.723A>T
NM_001276697.1:c.363A>T
NM_001276698.1:c.363A>T
NM_001276699.1:c.363A>T
NM_001276760.1:c.723A>T
NM_001276761.1:c.723A>T
NM_001276695.2:c.723A>T
NM_001276696.2:c.723A>T
NM_001276697.2:c.363A>T
NM_001276698.2:c.363A>T
NM_001276699.2:c.363A>T
NM_001276760.2:c.723A>T
NM_001276761.2:c.723A>T
NM_001126112.3:c.840A>T
NM_001126113.3:c.840A>T
NM_001126114.3:c.840A>T
NM_001126115.2:c.444A>T
NM_001126116.2:c.444A>T
NM_001126117.2:c.444A>T
NM_001126118.2:c.723A>T
NM_001276695.3:c.723A>T
NM_001276696.3:c.723A>T
NM_001276697.3:c.363A>T
NM_001276698.3:c.363A>T
NM_001276699.3:c.363A>T
NM_001276760.3:c.723A>T
NM_001276761.3:c.723A>T
More

Pathogenic

Met criteria codes 5
PS3 PM1_Supporting PP4_Moderate PP3_Moderate PM2_Supporting
Not Met criteria codes 8
PS2 PS4 BP4 PP1 BA1 BS2 BS4 BS1

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.840A>T variant in TP53 is a missense variant predicted to cause substitution of arginine by serine at amino acid 280 (p.Arg280Ser). Although this variant has been observed in a hypodiploid ALL case, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMIDs: 23334668, 26580448, 29489754, 32000721, 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 has an allele frequency of 0.00000062 (1/1613914 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (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 = 0.519515; 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 8 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: PP4_Moderate, PM2_Supporting, PS3, PP3_Moderate, PM1_Supporting. (Bayesian Points: 10; VCEP specifications version 2.4)
Met criteria codes
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).
PM1_Supporting
This variant has 8 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).
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).
PP3_Moderate
Computational predictor scores (BayesDel = 0.519515; 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 0.00000062 (1/1613914 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMIDs: 23334668, 26580448, 29489754, 32000721, Internal lab contributors).
BP4
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
BA1
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
BS4
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
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
ClinGen Terms of Use.
¤ Powered by BCM's Genboree.