TP53 c.246G>A, p.Pro82=
NM_000546.5:c.246G>A
COSMIC ID: COSM45229
Likely Benign
This synonymous TP53 c.246G>A (p.P82=) variant is absent or extremely rare in population databases (PM2_Supporting), has multiple benign computational/splice predictions (BP4_Supporting, BP7_Supporting), and is reported as benign by reputable sources (BP6_Supporting). No pathogenic or functional evidence exists. Based on three supporting benign criteria, the variant is classified as Likely Benign.
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_000546.5:c.246G>A
Protein Change
P82=
Location
Exon 4
(Exon 4 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM45229
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.246G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00142%
Rare
Highest in Population
African/African American
0.00821%
Rare
Global: 0.00142%
African/African American: 0.00821%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281738Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00142%, 4/281738 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00821%, 2/24372 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 12 submitter reviews in ClinVar
Submitter Breakdown
10 LB
2 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (10 clinical laboratories) and as Likely 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: -0.06
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 predicted null variants (nonsense, frameshift, canonical splice site) predicted to result in NMD.' The evidence for this variant shows: it is a synonymous change (p.P82=) not predicted to result in loss of function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'PS1 can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications.' The evidence for this variant shows: it does not alter the amino acid sequence and has no matching pathogenic amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'PS2 Very Strong Strength: ≥ 8 points; Strong: 4–7 points; Moderate: 2–3 points; Supporting: 1 point in de novo framework.' The evidence for this variant shows: no de novo segregation data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong Strength: Non-functional on Kato et al. data AND loss of function on another assay.' The evidence for this variant shows: no functional assay data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Very Strong Strength: ≥ 8 points; Strong: 4–7.5 points; Moderate: 2–3.5 points; Supporting: 1–1.5 points based on case counts.' The evidence for this variant shows: no case–control or proband data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: Missense variants within codons 175, 245, 248, 249, 273, 282 or germline variants seen as cancer hotspots.' The evidence for this variant shows: it is a synonymous change not at a hotspot codon. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'PM2 Supporting Strength: allele frequency < 0.00003 in gnomAD or another large database.' The evidence for this variant shows: MAF = 0.00142% (0.0000142) in gnomAD, which is below the 0.00003 threshold. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant shows: TP53 disorders are autosomal dominant and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: it 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, the rule for PM5 is: 'Strong/Moderate/Supporting Strength: Missense variant at a residue with ≥2/1/1 different missense variants previously determined to be pathogenic/likely pathogenic.' The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo (without confirmation of paternity/maternity).' The evidence for this variant shows: no de novo evidence is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting/Moderate/Strong Strength: Cosegregation observed in 3–4 / 5–6 / ≥7 meioses.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation where missense is a common mechanism.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Moderate/Supporting Strength: Missense or exonic variants with SpliceAI ≥ 0.2.' The evidence for this variant shows: SpliceAI = 0.02, below the 0.2 threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Moderate/Supporting Strength based on variant allele fractions in tumor data.' The evidence for this variant shows: no somatic VAF data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic but evidence not available for review.' The evidence for this variant shows: reputable sources report it as benign/likely benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Filtering allele frequency ≥ 0.001 (0.1%) in gnomAD continental subpopulations.' The evidence for this variant shows: MAF = 0.00142% (0.0000142), below the 0.1% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Filtering allele frequency ≥ 0.0003 but < 0.001 in gnomAD subpopulations.' The evidence for this variant shows: allele frequency = 0.0000142, below the 0.0003 threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong/Moderate/Supporting Strength: ≥8 / 4–7 / 2–3 unrelated females ≥60 years without cancer.' The evidence for this variant shows: no such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Functional on Kato et al. data AND no loss of function on another assay.' The evidence for this variant shows: no functional assay data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Strength: Lack of segregation in affected family members.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LOF is known mechanism.' 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, the rule for BP2 is: 'Observed in trans with a pathogenic variant in a dominant disorder.' The evidence for this variant shows: no trans data available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive region.' The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: Silent or intronic variants (outside ±1,2 positions) with SpliceAI ≤ 0.1.' The evidence for this variant shows: SpliceAI = 0.02, indicating no predicted splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence supports no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular cause.' The evidence for this variant shows: no such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign but evidence not available for independent review.' The evidence for this variant shows: ClinVar entries from multiple labs report it as Benign or Likely Benign. Therefore, this criterion is applied at Supporting strength because of reputable source assertion.
BP7
BP7 (Supporting)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: A synonymous (silent) variant outside of the core splice motif with SpliceAI ≤ 0.1.' The evidence for this variant shows: it is a silent change and SpliceAI = 0.02. Therefore, this criterion is applied at Supporting strength because no splicing impact is predicted.