TP53 c.671A>G, p.Glu224Gly
NM_000546.6:c.671A>G
COSMIC ID: COSM44014
Variant of Uncertain Significance (VUS)
The TP53 E224G variant lacks pathogenic hotspot location, functional data, and case segregation. It is absent from population databases but shows predicted splice impact. With only PM2_Supporting and PP3_Supporting, the evidence is insufficient, and the variant remains a VUS.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.671A>G
Protein Change
E224G
Location
Exon 6
(Exon 6 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 224 in gene TP53
Alternate Identifiers
COSM44014
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.671A>G
Active Tracks
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Uncertain Significance (VUS)
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
39
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (39 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 224 in gene TP53
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.89
0.89
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 6.17primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants or canonical splice variants predicted to undergo NMD in TP53. The variant is a missense change (E224G), not a null or splice variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the same amino acid change as a previously established TP53 pathogenic variant is observed. There is no report of a pathogenic E224G or equivalent amino acid change at codon 224. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo cases meeting point thresholds. No de novo data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires functional assay data demonstrating loss of function in TP53. No functional study results are available for E224G. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires proband counting to meet point thresholds. No case-level or segregation data are reported. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 Moderate applies to missense variants in TP53 hotspot codons (175, 245, 248, 249, 273, 282) or Supporting for 2–9 somatic occurrences. Codon 224 is not in the defined hotspots and has zero somatic occurrences. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting is: "Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population." The evidence shows this variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the allele frequency is below the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to detection in trans with a pathogenic variant for recessive disorders. TP53 disease is autosomal dominant and no trans observations are relevant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels or stop-loss). The variant is a missense change without length alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 Moderate applies when ≥2 different pathogenic missense changes at the same codon have been observed; PM5 Supporting when a single pathogenic missense is known. No pathogenic variants at codon 224 are reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. There is no de novo evidence. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires cosegregation in multiple meioses. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for genes where missense is a common mechanism and benign missense variation is low. TP53 has many known pathogenic missense variants; the rule is not met. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 Supporting is: "Exonic (including silent variants and apparent 'missense' variants) with predicted splice effect: SpliceAI ≥ 0.2." The evidence shows a SpliceAI donor loss score of 0.73. Therefore, PP3 is applied at Supporting strength because SpliceAI ≥ 0.2 indicates a predicted splice effect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies for specific variant allele fraction observations in somatic contexts. Germline phenotype data are not provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 (reputable source assertion) is not used per ACMG/AMP recommendations. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at FAF ≥ 0.001 in gnomAD. The variant is absent in gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong applies at FAF ≥ 0.0003 but <0.001. The variant is absent in gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation in ≥8 healthy older females. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional data showing retained function. No functional assays for E224G are reported. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in multiple affected family members. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only LOF causes disease. TP53 disease mechanism includes dominant negative missense effects. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for a dominant disorder. No such observations are reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires benign computational evidence (BayesDel ≤ -0.008 and SpliceAI < 0.2). The variant has damaging predictions and SpliceAI ≥ 0.2. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when an alternate molecular cause is identified. No alternate cause is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 (low-confidence assertion) is not recommended. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous variants with no splicing impact. This is a missense variant. Therefore, BP7 is not applied.