TP53 c.787A>G, p.Asn263Asp
NM_000546.6:c.787A>G
COSMIC ID: COSM45752
Variant of Uncertain Significance (VUS)
The TP53 NM_000546.6:c.787A>G (N263D) variant remains classified as a VUS. Functional studies (BS3 Strong) indicate preserved TP53 activity, and benign computational evidence (BP4 Supporting) further supports a benign impact. However, the allele frequency does not meet the strict VCEP threshold for PM2, and there is insufficient additional evidence to classify the variant as benign or pathogenic.
ACMG/AMP Criteria Applied
BS3
BP4
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.787A>G
Protein Change
N263D
Location
Exon 8
(Exon 8 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 263 in gene TP53
Alternate Identifiers
COSM45752
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.787A>G
Active Tracks
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Clinical Data
Global Frequency
0.0114%
Low Frequency
Highest in Population
South Asian
0.0829%
Common
Global: 0.0114%
South Asian: 0.0829%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 246378Alt: 28Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0114%, 28/246378 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.0829%, 25/30148 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
5 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Uncertain significance (4 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 263 in gene TP53
Functional Summary
The TP53 N263D variant has been functionally characterized and demonstrates DNA-binding activity, induction of apoptosis, and activation of STAT4 mRNA expression at levels similar to wild-type TP53. This suggests that the N263D variant does not impair the functional activities typically associated with TP53.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.315
0.315
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
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 1.52polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Null Variant (nonsense, frameshift, etc.) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows that it is a missense change (N263D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant does not indicate such a match. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' There is no de novo data provided for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard evaluation and the provided pipeline evidence, the rule for PS3 involves demonstrating loss of function through functional studies. The evidence for this variant shows normal DNA-binding activity, apoptosis induction, and activation of STAT4 mRNA expression similar to wild-type TP53. Therefore, PS3 is not applied as pathogenic evidence.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires significant case-control data or multiple independent observations in affected individuals. The evidence for this variant does not provide such data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Missense variants within specific hotspot codons (175, 245, 248, 249, 273, 282)'. The evidence for this variant (N263D) shows that it is not located in one of these codons. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting Strength) is: 'Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large control dataset.' The evidence shows a MAF of 0.0114% (0.000114 overall and 0.0829% in the South Asian population), which exceeds the threshold. Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is applied to recessive disorders where detection in trans with a pathogenic variant is required. Since TP53 is associated with a dominant mode of inheritance, this criterion is not applicable. Therefore, it is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 applies to inframe indels or stop-loss variants that lead to change in protein length. The evidence for this variant shows a missense change rather than an inframe deletion or insertion. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Missense variant at an amino acid residue where ≥2 (or 1 for Moderate, if appropriately supported) different missense variants have been determined to be pathogenic.' The evidence does not indicate any such precedent at residue 263. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is used for de novo occurrences when parental confirmation is not available. Since no de novo information is provided for this variant, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 requires co-segregation in multiple affected family members (≥3–4 meioses for Supporting). There is no segregation data provided for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease. For TP53, missense variants occur frequently and the benign background is complex. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (computational evidence suggesting deleterious impact) should not be combined with BP4 when benign computational evidence is present. The evidence for this variant shows mixed in silico predictions with overall benign computational support, meeting BP4. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires the patient’s phenotype or family history to be highly specific for a disease with a single genetic etiology. There is no such specific phenotype or family history provided for this variant. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to VCEP guidelines, PP5 is for variants reported as pathogenic by reputable sources without available primary data. The evidence for this variant comes from multiple laboratory reports with conflicting interpretations (Likely benign and VUS) and does not support PP5. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 is a stand-alone benign criterion defined by an allele frequency greater than or equal to 0.001 (0.1%) in a continental population. The variant’s allele frequency is below this threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 is applied when the allele frequency is greater than expected for the disorder (≥0.0003 but <0.001 in gnomAD continental subpopulations). The variant’s frequency does not reach that level. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 is used when the variant is observed in multiple healthy individuals beyond a certain age without the disease. There is no such data provided for this variant. Therefore, BS2 is not applied.
BS3
BS3 (Strong)
According to VCEP guidelines for BS3, the rule is: 'Strong: Functional evidence from multiple assays demonstrating that the variant does not impair function (e.g., normal DNA-binding, apoptosis induction, etc.).' The evidence for this variant shows that the TP53 N263D has normal DNA-binding activity, normal induction of apoptosis, and STAT4 activation similar to wild-type TP53. Therefore, BS3 is applied at Strong strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires a lack of segregation with disease in affected family members. There is no segregation data provided for this variant. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants in genes where truncating variants are known to cause disease, suggesting that missense variants are less likely to be pathogenic. Although TP53 often has pathogenic missense variants, the evidence does not specifically support BP1 in this case. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 is applied when the variant is observed in trans with a pathogenic variant or in a context that argues against a pathogenic role. There is no such information for this variant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 is for inframe deletions in repetitive regions with no known function. This rule is not applicable for a missense variant like N263D. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BP4, the rule is: 'Supporting: Missense variants with computational evidence (e.g., CADD, PolyPhen, SpliceAI) indicating no predicted deleterious effect, with BayesDel score < 0.16 and no splicing impact (SpliceAI < 0.2).' The evidence for this variant shows mixed computational predictions overall leaning toward benign effects (e.g., a CADD score of 1.52, benign PolyPhen, and SpliceAI score of 0.12). Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 is applied if there is an alternate molecular basis for the phenotype. There is no evidence provided for such an alternate cause in this case. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to VCEP guidelines, BP6 is for variants reported as benign by reputable sources without available primary data. Although ClinVar shows conflicting interpretations, this does not meet the strict criteria for BP6. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no predicted splicing effect. Since this variant is a missense variant, BP7 is not applicable. Therefore, BP7 is not applied.