TP53 c.1053G>T, p.Lys351Asn
NM_000546.6:c.1053G>T
COSMIC ID: COSM3362446
Variant of Uncertain Significance (VUS)
The variant NM_000546.6:c.1053G>T (p.K351N) in TP53 is absent from population databases (PM2_Supporting) and has limited computational evidence favoring benign (BP4_Supporting). No additional supportive or contrary evidence is available; the combination of one supporting pathogenic and one supporting benign criterion results in a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
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.1053G>T
Protein Change
K351N
Location
Exon 10
(Exon 10 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 351 in gene TP53
Alternate Identifiers
COSM3362446
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.1053G>T
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
1 publications
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 822085). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 protein function (PMID: 12826609, 21953469). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces lysine with asparagine at codon 351 of the TP53 protein (p.Lys351Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine.
Clinical Statement
This variant has been reported in ClinVar 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 351 in gene TP53
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.463
0.463
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: 3.04primateai: 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 only to null variants (nonsense, frameshift, canonical splice, initiation codon, or deletions) in TP53; this is a missense variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires the same amino acid change as a previously established pathogenic variant. There are no reported pathogenic variants resulting in K351N. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 requires confirmed de novo occurrence with maternity and paternity confirmed. No de novo data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 applies to functional assays demonstrating loss of function. No functional characterization is available for K351N. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case‐level or proband point totals meeting thresholds. No case data or proband counts are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants within known mutational hotspots (codons 175, 245, 248, 249, 273, 282) or ≥10 somatic occurrences at the same residue. K351 is outside these hotspots. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting: allele frequency <0.00003 in gnomAD. The variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with variants observed in trans. TP53‐related disease is autosomal dominant and no trans data exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length–altering variants (inframe indels, stop-loss). This is a missense change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to a missense at a residue with ≥1 known pathogenic missense. No other pathogenic variants at K351 are reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to unconfirmed de novo events. No parental data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data (3–4 meioses for Supporting). No family segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when missense variants are a common mechanism and gene is constrained for missense. TP53 has both missense and truncating disease mechanisms and is not clearly constrained. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires aGVGD C65 and BayesDel ≥0.16 or SpliceAI ≥0.2 for splicing. BayesDel not provided and SpliceAI predicts no splicing effect. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a specific phenotype or family history highly specific to TP53-related disorder. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies the variant as pathogenic. ClinVar reports this variant as VUS. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 applies to allele frequency ≥5% in controls. The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when filtering allele frequency ≥0.0003. The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires ≥2 unrelated females ≥60 years old without cancer. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional assays showing no loss of function. No functional data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in 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 in a gene where only truncating variants cause disease. TP53 has many pathogenic missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant observed in trans with a pathogenic variant in a dominant disorder. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to inframe indels in repetitive regions. This is a missense change. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4: multiple lines of computational evidence suggest no impact on gene or gene product. In silico predictors are mixed but SpliceAI predicts no splicing impact, supporting a benign interpretation. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in a case with an alternate molecular cause. No such data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source classifies the variant as benign. No benign assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies only to synonymous or intronic variants with no splicing impact. This is a missense variant. Therefore, BP7 is not applied.