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.857A>T (p.Glu286Val)

CA16603014

376592 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 8d37f3ab-2635-42d8-a422-ed44f21e256d
Approved on: 2026-08-06
Published on: 2026-09-22

HGVS expressions

NM_000546.6:c.857A>T
NM_000546.6(TP53):c.857A>T (p.Glu286Val)
NC_000017.11:g.7673763T>A
CM000679.2:g.7673763T>A
NC_000017.10:g.7577081T>A
CM000679.1:g.7577081T>A
NC_000017.9:g.7517806T>A
NG_017013.2:g.18788A>T
ENST00000503591.2:c.857A>T
ENST00000508793.6:c.857A>T
ENST00000509690.6:c.461A>T
ENST00000514944.6:c.578A>T
ENST00000604348.6:c.836A>T
ENST00000269305.9:c.857A>T
ENST00000269305.8:c.857A>T
ENST00000359597.8:c.857A>T
ENST00000413465.6:c.782+418A>T
ENST00000420246.6:c.857A>T
ENST00000445888.6:c.857A>T
ENST00000455263.6:c.857A>T
ENST00000504290.5:c.461A>T
ENST00000504937.5:c.461A>T
ENST00000509690.5:c.461A>T
ENST00000510385.5:c.461A>T
ENST00000610292.4:c.740A>T
ENST00000610538.4:c.740A>T
ENST00000610623.4:c.380A>T
ENST00000615910.4:c.824A>T
ENST00000617185.4:c.857A>T
ENST00000618944.4:c.380A>T
ENST00000619186.4:c.380A>T
ENST00000619485.4:c.740A>T
ENST00000620739.4:c.740A>T
ENST00000622645.4:c.740A>T
ENST00000635293.1:c.740A>T
NM_000546.5:c.857A>T
NM_001126112.2:c.857A>T
NM_001126113.2:c.857A>T
NM_001126114.2:c.857A>T
NM_001126115.1:c.461A>T
NM_001126116.1:c.461A>T
NM_001126117.1:c.461A>T
NM_001126118.1:c.740A>T
NM_001276695.1:c.740A>T
NM_001276696.1:c.740A>T
NM_001276697.1:c.380A>T
NM_001276698.1:c.380A>T
NM_001276699.1:c.380A>T
NM_001276760.1:c.740A>T
NM_001276761.1:c.740A>T
NM_001276695.2:c.740A>T
NM_001276696.2:c.740A>T
NM_001276697.2:c.380A>T
NM_001276698.2:c.380A>T
NM_001276699.2:c.380A>T
NM_001276760.2:c.740A>T
NM_001276761.2:c.740A>T
NM_001126112.3:c.857A>T
NM_001126113.3:c.857A>T
NM_001126114.3:c.857A>T
NM_001126115.2:c.461A>T
NM_001126116.2:c.461A>T
NM_001126117.2:c.461A>T
NM_001126118.2:c.740A>T
NM_001276695.3:c.740A>T
NM_001276696.3:c.740A>T
NM_001276697.3:c.380A>T
NM_001276698.3:c.380A>T
NM_001276699.3:c.380A>T
NM_001276760.3:c.740A>T
NM_001276761.3:c.740A>T
More

Pathogenic

Met criteria codes 6
PS3 PM1_Supporting PP4 PM5 PP3_Moderate PM2_Supporting
Not Met criteria codes 20
PS2 PS4 PS1 BP2 BP3 BP4 BP1 BP5 BP7 PP1 PP2 PVS1 PM6 PM3 PM4 BA1 BS2 BS4 BS3 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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.857A>T variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by valine at amino acid 286 (p.Glu286Val). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). In addition, this variant received a total of 0.5 points across 1 proband (PS4 not met; 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). Another missense variant(c.857A>G, p.Glu286Gly) (ClinVar Variation ID: 376590), with Grantham score equal to or less than the current variant in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.4044; 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 3 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: PS3, PM5, PP3_Moderate, PM1_Supporting, PM2_Supporting, PP4. (Bayesian Points: 11; 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 3 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
At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors).
PM5
Another missense variant(c.857A>G, p.Glu286Gly) (ClinVar Variation ID: 376590), with Grantham score equal to or less than the current variant in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5).
PP3_Moderate
Computational predictor scores (BayesDel = 0.4044; 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).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (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
This variant received a total of 0.5 points across 1 proband (PS4 not met; Internal lab contributors).
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
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
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
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.