TP53 c.1012T>C, p.Phe338Leu
NM_000546.6:c.1012T>C
Variant of Uncertain Significance (VUS)
p.F338L in TP53 is absent from population databases (PM2_Supporting) but lacks additional evidence for pathogenic or benign classification; therefore it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
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.1012T>C
Protein Change
F338L
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 338 in gene TP53
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.1012T>C
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 338 in gene TP53
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.681
0.681
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: 4.36primateai: 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: 'PVS1 applies to null variants (nonsense, frameshift, canonical ±1,2 splice, initiation codon) predicted to result in loss of function.' The evidence for this variant shows: it is a missense change (p.F338L), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a predicted null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'PS1 applies to variants resulting in the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: there is no previously established pathogenic variant at residue F338. Therefore, this criterion is not applied at Not Applied strength because the amino acid change is novel.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'PS2 requires confirmed de novo occurrence (both maternity and paternity confirmed).' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'PS3 applies when well-established functional assays demonstrate a damaging effect on the gene or gene product.' The evidence for this variant shows: no functional studies have been performed for p.F338L. Therefore, this criterion is not applied at Not Applied strength because functional data are missing.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'PS4 applies when there is a statistically significant increase in variant prevalence in affected individuals compared to controls (case points ≥ 1 required for Supporting).' The evidence for this variant shows: no case or proband data are available. Therefore, this criterion is not applied at Not Applied strength because case occurrence data are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'PM1 applies to missense variants within established TP53 hotspots (codons 175, 245, 248, 249, 273, 282) or somatic hotspots with ≥10 occurrences.' The evidence for this variant shows: p.F338L affects codon 338, which is outside these hotspots. Therefore, this criterion is not applied at Not Applied strength because the residue is not in a defined hotspot.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'PM2 (Supporting) applies if the variant allele frequency is <0.00003 in gnomAD.' The evidence for this variant shows: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the allele frequency meets the threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'PM3 applies to variants detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant shows: TP53 is associated with a dominant mechanism, and no trans observations are relevant. Therefore, this criterion is not applied at Not Applied strength because PM3 is not relevant for this dominant gene.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'PM4 applies to protein length–altering variants (in-frame indels) not affecting splicing.' The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'PM5 (Moderate) applies to a novel missense change at a residue where ≥1 different missense variant previously determined to be pathogenic has been seen.' The evidence for this variant shows: no pathogenic missense variants at residue F338 have been established. Therefore, this criterion is not applied at Not Applied strength because there is no prior pathogenic variant at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'PM6 (Supporting) applies to assumed de novo variants without confirmation of parentage.' The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'PP1 applies to cosegregation of variant with disease in families (Supporting: 3–4 meioses; Moderate: 5–6; Strong: ≥7).' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied at Not Applied strength because family segregation has not been assessed.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'PP2 applies to missense variants in a gene with low rate of benign missense variation where missense is a common mechanism.' The evidence for this variant shows: TP53 has many benign and pathogenic missense variants, not a low benign variation context. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'PP3 (Moderate) applies to missense variants with BayesDel ≥0.16 and no predicted splicing impact.' The evidence for this variant shows: BayesDel score is unavailable, and computational predictions are mixed. Therefore, this criterion is not applied at Not Applied strength because required BayesDel data are lacking.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'PP4 (Supporting) applies when the phenotype is highly specific for a single gene disorder.' The evidence for this variant shows: no patient phenotype data are provided. Therefore, this criterion is not applied at Not Applied strength because phenotype information is absent.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'PP5 applies when a reputable source reports the variant as pathogenic but the evidence is unavailable.' The evidence for this variant shows: no such reputable assertions exist. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'BA1 (Stand Alone) applies if allele frequency ≥0.001 in any gnomAD continental subpopulation.' The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is below the threshold.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'BS1 (Strong) applies if filtering allele frequency ≥0.0003 but <0.001 in gnomAD.' The evidence for this variant shows: absent in gnomAD. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is below the threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'BS2 applies when ≥2 unrelated healthy individuals ≥60 years without cancer carry the variant.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength because healthy adult carrier data are unavailable.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'BS3 (Strong) applies when functional assays demonstrate no loss of function.' The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied at Not Applied strength because no functional evidence of preserved function exists.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'BS4 (Strong) applies when there is lack of segregation with disease in affected family members.' The evidence for this variant shows: no segregation analysis. Therefore, this criterion is not applied at Not Applied strength because family data are missing.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'BP1 applies to missense variants in a gene where only truncating variants cause disease.' The evidence for this variant shows: TP53 disease mechanism commonly involves missense. Therefore, this criterion is not applied at Not Applied strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'BP2 applies when variant is observed in cis or trans with a pathogenic variant for a dominant gene without phenotype.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied at Not Applied strength.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'BP3 applies to in-frame indels in repetitive regions without a known function.' The evidence for this variant shows: it is a missense substitution outside repetitive sequence. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'BP4 (Moderate) applies to missense variants with BayesDel ≤ –0.008 and SpliceAI <0.2.' The evidence for this variant shows: SpliceAI <0.2 but BayesDel unavailable. Therefore, this criterion is not applied at Not Applied strength because BayesDel data are lacking.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'BP5 applies when a variant is found in a gene for which the patient phenotype is explained by another variant.' The evidence for this variant shows: no such alternate explanation. Therefore, this criterion is not applied at Not Applied strength.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'BP6 applies when a reputable source reports the variant as benign but the evidence is unavailable.' The evidence for this variant shows: no such assertions exist. Therefore, this criterion is not applied at Not Applied strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'BP7 applies to synonymous or intronic variants outside core splice sites with no predicted splicing impact.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied at Not Applied strength.