TP53 c.1136G>A, p.Arg379His
NM_000546.6:c.1136G>A
COSM44189
Population Frequency
0.000707%
Rare
ClinVar Classification
Uncertain Significance (VUS)
6 publications
REVEL Score
0.338
Uncertain (Low)
COSMIC Recurrence
5 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.1136G>A
Protein Change
R379H
Location
Exon 11
(Exon 11 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 379 in gene TP53
Alternate Identifiers
COSM44189
Variant interpretation based on transcript NM_000546.6
Clinical Evidence
Global Frequency
0.000707%
Very Rare
Highest in Population
African/African American
0.00401%
Rare
Global: 0.000707%
African/African American: 0.00401%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 282792
Alt: 2
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000707%, 2/282792 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00401%, 1/24960 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
6 publications
Uncertain Significance (VUS)
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
6 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratories) and as Uncertain Significance (1 clinical laboratories) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Likely Benign
ClinGen TP53 Variant Curation Expert Panel, ClinGen
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 379 in gene TP53
Functional Studies
Summary
The TP53 R379H variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.338
0.338
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, splice site alterations leading to NMD) in TP53. The rule states: 'PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351.' The evidence for this variant shows a missense change (R379H), which is not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS1 is applied when the same amino acid change as a previously established pathogenic variant is observed regardless of nucleotide change. The evidence for this variant shows R379H without confirmation of being identical to a known pathogenic amino acid change from another nucleotide change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines for PS2, de novo occurrence (with confirmed parentage) in a patient with the disease is required. The evidence for this variant does not include de novo status. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines (and noting PTEN pre‐processing rules are not applicable for TP53), PS3 requires well-established functional studies demonstrating a damaging effect. The provided functional studies indicate that the TP53 R379H variant has not been functionally characterized. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PS4 is applied if there is a significant case–control statistical enrichment of the variant in affected individuals. The evidence for this variant does not include case–control data or proband point accumulation. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, PM1 is applied for missense variants within established hotspot codons (175, 245, 248, 249, 273, 282). The variant R379H is located outside of these codons. The evidence for this variant shows its position in the C-terminal domain but not in a hotspot region per VCEP specifications. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to TP53 VCEP guidelines for PM2, the rule should be applied at a Supporting level for variants with an allele frequency below the specified threshold (less than 0.00003 in gnomAD). The rule states: 'This rule should be applied at supporting level.' The evidence for this variant shows a MAF of 0.000707% (which, when converted appropriately, remains below the threshold) and absence of homozygotes, supporting application of PM2 at a Supporting strength. Therefore, this criterion is applied.
PM3
PM3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM3 is applicable to variants in recessive disorders in the context of compound heterozygosity. TP53 is associated with an autosomal dominant disorder and the evidence does not include compound heterozygosity. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM4 relates to protein length changes due to in-frame deletions/insertions or stop-loss variants. The evidence for this variant indicates a missense change rather than an in-frame indel or length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, PM5 is applied if a different missense change at the same residue has been previously classified as pathogenic. The evidence for this variant does not include any previously established pathogenic missense change at amino acid residue 379. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PM6 is a de novo criterion similar to PS2 but with lower point assignment where complete parentage confirmation may not be available. The evidence for this variant does not include any de novo findings. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, PP1 relates to cosegregation data in families. The rule requires segregation in multiple affected meioses. The evidence for this variant does not include any segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP2 is applicable for missense variants in genes with a low rate of benign missense variation and where missense variants are a common mechanism of disease. The evidence for TP53 does not specifically support application of PP2 in this case. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines for PP3 and BP4, PP3 is applied when in silico tools predict a deleterious effect. The rule states: 'Supporting Missense variants... with aGVGD class C25-C55 and BayesDel score ≥ 0.16' or SpliceAI ≥ 0.2 for splicing. The evidence for this variant shows conflicting computational predictions with a REVEL score of 0.34 and a SpliceAI score of 0.08, which does not meet criteria for a deleterious impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP4 is used when the patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. The evidence for this variant does not include any phenotype-specific observations. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, PP5 is applied when a reputable source has reported the variant as pathogenic without providing detailed evidence. The evidence for this variant shows conflicting interpretations from ClinVar (VUS and likely benign) and therefore does not fulfill PP5. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, BA1 is a stand-alone benign criterion if the allele frequency is ≥0.1% in a relevant population. The evidence for this variant shows a very low allele frequency (0.000707%), which is well below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, BS1 is applied if the allele frequency is greater than expected for the disorder (≥0.03% but <0.1%). The evidence for this variant demonstrates a frequency that is much lower than this threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, BS2 is applied when the variant is observed in multiple healthy adult individuals beyond a specified age without disease. The evidence for this variant does not provide such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines and TP53 VCEP modifications for BS3, this criterion is applied when functional studies demonstrate no loss of function. The provided functional evidence for this variant indicates that it has not been functionally characterized. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, BS4 is applied when there is a lack of segregation in affected family members. The evidence for this variant does not include segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP1 is applied for missense variants in a gene for which truncating variants are known to cause disease, provided missense variants are not a common mechanism. For TP53, missense variants are commonly observed. The evidence for this variant does not support BP1. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP2 is applied when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a known pathogenic variant for an autosomal recessive disorder. The evidence for this variant does not include such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to Standard ACMG guidelines, BP3 is used for in-frame deletions/insertions in repetitive regions without a known function. The evidence for this variant, being a missense change, does not support BP3. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to TP53 VCEP guidelines for BP4, the criterion is applied if in silico predictions do not support a deleterious effect, specifically when tools such as SpliceAI predict no splicing alterations (score below 0.2) and other computational measures do not indicate a damaging change. The rule states: 'Supporting Strength: Supporting Missense variants ... with no predicted differences in splicing (SpliceAI < 0.2)'. The evidence for this variant shows a REVEL score of 0.34 (which in context does not cross a consensus pathogenic threshold) and a SpliceAI score of 0.08, indicating minimal impact on splicing. Therefore, this criterion is applied at a Supporting strength.
BP7
BP7 (Not Applied)
Strength Modified
According to TP53 VCEP guidelines, BP7 is applied to synonymous or intronic variants outside of the core splice motif with no predicted impact on splicing. The evidence for this variant shows a missense change, not a synonymous alteration, and therefore BP7 is not applicable. Therefore, this criterion is not applied.