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]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.869G>A (p.Arg290His)

CA000468

127825 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: de5ede53-7b6d-40ad-8a0e-0b3aa4c7ecd8
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.869G>A
NM_000546.5(TP53):c.869G>A (p.Arg290His)
NC_000017.11:g.7673751C>T
CM000679.2:g.7673751C>T
NC_000017.10:g.7577069C>T
CM000679.1:g.7577069C>T
NC_000017.9:g.7517794C>T
NG_017013.2:g.18800G>A
ENST00000503591.2:c.869G>A
ENST00000508793.6:c.869G>A
ENST00000509690.6:c.473G>A
ENST00000514944.6:c.590G>A
ENST00000604348.6:c.848G>A
ENST00000269305.9:c.869G>A
ENST00000269305.8:c.869G>A
ENST00000359597.8:c.869G>A
ENST00000413465.6:c.782+430G>A
ENST00000420246.6:c.869G>A
ENST00000445888.6:c.869G>A
ENST00000455263.6:c.869G>A
ENST00000504290.5:c.473G>A
ENST00000504937.5:c.473G>A
ENST00000509690.5:c.473G>A
ENST00000510385.5:c.473G>A
ENST00000610292.4:c.752G>A
ENST00000610538.4:c.752G>A
ENST00000610623.4:c.392G>A
ENST00000615910.4:c.836G>A
ENST00000617185.4:c.869G>A
ENST00000618944.4:c.392G>A
ENST00000619186.4:c.392G>A
ENST00000619485.4:c.752G>A
ENST00000620739.4:c.752G>A
ENST00000622645.4:c.752G>A
ENST00000635293.1:c.752G>A
NM_001126112.2:c.869G>A
NM_001126113.2:c.869G>A
NM_001126114.2:c.869G>A
NM_001126115.1:c.473G>A
NM_001126116.1:c.473G>A
NM_001126117.1:c.473G>A
NM_001126118.1:c.752G>A
NM_001276695.1:c.752G>A
NM_001276696.1:c.752G>A
NM_001276697.1:c.392G>A
NM_001276698.1:c.392G>A
NM_001276699.1:c.392G>A
NM_001276760.1:c.752G>A
NM_001276761.1:c.752G>A
NM_001276695.2:c.752G>A
NM_001276696.2:c.752G>A
NM_001276697.2:c.392G>A
NM_001276698.2:c.392G>A
NM_001276699.2:c.392G>A
NM_001276760.2:c.752G>A
NM_001276761.2:c.752G>A
NM_000546.6:c.869G>A
NM_001126112.3:c.869G>A
NM_001126113.3:c.869G>A
NM_001126114.3:c.869G>A
NM_001126115.2:c.473G>A
NM_001126116.2:c.473G>A
NM_001126117.2:c.473G>A
NM_001126118.2:c.752G>A
NM_001276695.3:c.752G>A
NM_001276696.3:c.752G>A
NM_001276697.3:c.392G>A
NM_001276698.3:c.392G>A
NM_001276699.3:c.392G>A
NM_001276760.3:c.752G>A
NM_001276761.3:c.752G>A

Benign

Met criteria codes 3
BP4 BS2 BS3
Not Met criteria codes 20
PP1 PP3 PP4 PS1 PS4 PS2 PS3 PM1 PM5 PM4 PM3 PM2 BA1 PVS1 BP3 BP2 BP7 BP5 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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
BP4
Computational predictor scores (BayesDel = 0.09; Align GVGD Class 0) are below the recommended thresholds (BayesDel < 0.16 and > -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4).
BS2
This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000187277.8).
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).
Not Met criteria codes
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PS4
This variant has been observed in 2 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs: 10435620, 19468865) but this evidence is not applied as PM2_Supporting is not applied.
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
IARC database calls this supertrans & 2 studies show no effect on protein.
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
PM5
4 different missense variants (p.Arg290Leu; p.Arg290Pro; p.Arg290Gly; p.Arg290Cys) in the same codon have been reported (ClinVar Variation IDs: 633445, 458572, 628970, 216472). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
PM4
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
PM2
The highest population minor allele frequency in gnomAD v41.0 is 0.0002602 (307/1180030 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
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
BP3
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
BP7
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
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
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