TP53 c.246G>T, p.Pro82=
NM_000546.6:c.246G>T
Likely Benign
NM_000546.6:c.246G>T is a synonymous TP53 variant with no predicted impact on splicing or protein, absent from population databases, and supported by multiple benign computational and literature-based criteria (BP4, BP6, BP7) with no pathogenic evidence, leading to a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
BP7
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.246G>T
Protein Change
P82=
Location
Exon 4
(Exon 4 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.246G>T
Active Tracks
ConservationRefSeqClinVargnomAD
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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
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Benign (1 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.59
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 predicted to result in nonsense-mediated decay (nonsense variants upstream of p.Lys351 and frameshift induced premature termination codon upstream of p.Lys351)'. The evidence for this variant shows: c.246G>T is a synonymous (silent) change with no predicted null effect. Therefore, this criterion is not applied because the variant does not create a loss-of-function null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 can be applied when a variant results in the same amino acid change as a known pathogenic variant. The evidence for this variant shows: c.246G>T does not alter the amino acid (P82=). Therefore, this criterion is not applied because there is no amino acid change matching a known pathogenic variant.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 applies to confirmed de novo variants with appropriate parental testing. The evidence for this variant shows: no de novo data or parental testing available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 applies to well-validated functional studies showing a deleterious effect. The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional data are not available.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when case-control or proband data meet specified point thresholds for pathogenicity. The evidence for this variant shows: no case-control or proband statistical data. Therefore, this criterion is not applied due to absence of epidemiological evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants in established functional hotspots or critical domains. The evidence for this variant shows: c.246G>T is synonymous and not in a missense hotspot. Therefore, this criterion is not applied because the variant does not alter an amino acid in a critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting is applied when a variant has an allele frequency <0.00003 in gnomAD and related databases. The evidence for this variant shows: c.246G>T is absent from gnomAD and other control databases. Therefore, this criterion is applied at Supporting strength because the variant is absent or extremely rare in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants observed in trans with a pathogenic variant for a recessive disorder. The evidence for this variant shows: no data on trans observation with a pathogenic variant. Therefore, this criterion 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 evidence for this variant shows: c.246G>T is a synonymous change with no alteration in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at residues with previously established pathogenic missense variants. The evidence for this variant shows: no amino acid change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to assumed de novo cases without parental confirmation. The evidence for this variant shows: no de novo or family information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to demonstrated cosegregation in multiple affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to missense variants with computational evidence supporting a deleterious effect. The evidence for this variant shows: in silico tools predict no impact and SpliceAI score 0.06. Therefore, this criterion is not applied because computational evidence supports benign impact.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies when the patient phenotype is highly specific for a single genetic etiology. The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source classifies a variant as pathogenic without evidence. The evidence for this variant shows: sources classify it as benign/likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to variants with a filtering allele frequency ≥0.001 in gnomAD continental subpopulations. The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to variants with a filtering allele frequency ≥0.0003 but <0.001 in gnomAD. The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when ≥8 unrelated older females without cancer carry the variant. The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies to functional assays showing no loss of function. The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only loss-of-function causes disease. The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to variants observed in trans with a pathogenic variant for a dominant disorder. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions without functional impact. The evidence for this variant shows: it is not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4_Supporting for silent or intronic variants is applied when SpliceAI ≤0.1 and BP4 is met. The evidence for this variant shows: SpliceAI score 0.06 predicting no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence predicts no effect on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis. The evidence for this variant shows: no reports of alternate molecular causes. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without available evidence. The evidence for this variant shows: ClinVar submissions from two clinical laboratories classify it as benign/likely benign without available supporting data. Therefore, this criterion is applied at Supporting strength because of reputable but unevaluated benign assertions.
BP7
BP7 (Supporting)
According to VCEP guidelines, BP7_Supporting applies to synonymous variants outside core splice sites with SpliceAI ≤0.1 when BP4 is met. The evidence for this variant shows: c.246G>T is synonymous outside the core splice motif and SpliceAI score 0.06. Therefore, this criterion is applied at Supporting strength because no splicing impact is predicted.