The TP53 c.1136G>A (p.Arg379His) variant has been reported in ClinVar, including a Likely Benign expert-panel assertion from the ClinGen TP53 Variant Curation Expert Panel.1 This variant is rare in population databases, with a gnomAD v4.1 total allele frequency of 4.95699e-06 and joint grpmax filtering allele frequency of 4.43e-06, which supports PM2_Supporting and is below the BS1 and BA1 thresholds.2 In published TP53 functional studies summarized by the TP53 VCEP functional worksheet, p.Arg379His was functional in the Kato assay set and showed no loss of function in the Giacomelli assay set, supporting BS3 and arguing against PS3.3 TP53 VCEP in silico assessment supports a benign computational effect: the variant is assigned BP4_moderate in the TP53 bioinformatic worksheet, BayesDel is -0.0720003, SpliceAI shows no significant splice effect, and REVEL is 0.338.4
Final classification
Likely Benign
PM2BP6BS3BP4
TP53
c.1136G>A
p.Arg379His
This variant
The TP53 c.1136G>A (p.Arg379His) variant has been reported in ClinVar, including a Likely Benign expert-panel assertion from the ClinGen TP53 Variant Curation Expert Panel.
Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: BS3 strong (-4) + BP4 moderate (-2) + PM2 supporting (+1) + BP6 supporting benign (-1) = -6 points, which maps to Likely Benign.
Classification rationale
PM2
BP6BS3BP4
Likely Benign
TP53 c.1136G>A
PM2 + BP6 + BS3 + BP4
→
Likely Benign
3
vcep_functional_worksheetPMID:12826609 ↗PMID:30224644 ↗cspec ↗
4
vcep_pp3_bp4_codesbayesdelspliceai ↗revelcspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
This variant is rare in population databases and meets the TP53 VCEP PM2 threshold. In gnomAD v4.1, the total allele frequency is 4.95699e-06, which is below the PM2 cutoff of 0.00003, and the joint grpmax filtering allele frequency is 4.43e-06. In gnomAD v2.1, the total allele frequency is 7.07234e-06, also below the threshold.
gnomAD v4.1 total AF 4.95699e-06joint grpmax FAF 4.43e-06.gnomAD v2.1 total AF 7.07234e-06.
BS3
strong
review
Benign
Published TP53 functional evidence supports a benign effect. In the TP53 VCEP functional worksheet, p.Arg379His is classified as functional in the Kato assay set and as no loss of function in the Giacomelli assay set, with a pre-assigned BS3 code.
Functional worksheet row: R379H -> Kato FunctionalGiacomelli noLOFpreliminary functional code BS3.
BP4
moderate
review
Benign
Computational evidence supports a benign effect under the TP53 VCEP missense rules. The TP53 VCEP bioinformatic worksheet assigns BP4_moderate for c.1136G>A with Align-GVGD class C0 and BayesDel -0.0720003, which is below the BP4_moderate cutoff of -0.008, and there is no predicted splice impact (worksheet SpliceAI 0.08; case SpliceAI max delta score 0.00, both below 0.2). REVEL is available at 0.338 and does not contradict the benign VCEP bioinformatic assignment.
PP3/BP4 worksheet row: c.1136G>A -> BP4_moderate.BayesDel score -0.0720003.Worksheet SpliceAI 0.08 and case SpliceAI max delta 0.00.
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PVS1
This variant is a missense substitution and does not fall into the TP53 PVS1 null-variant categories.
PS1
No independently established TP53 VCEP pathogenic or likely pathogenic variant causing the same amino acid change was identified from the available evidence, so PS1 was not assessed.
PS2
No confirmed de novo occurrence data with a TP53 VCEP point tally were identified for this variant.
PS3
Available functional evidence does not support loss of function for this variant.
PS4
This variant meets the TP53 VCEP population prerequisite for PS4 because the gnomAD allele frequency is below the PM2 threshold, but no proband-based Li-Fraumeni syndrome point tally was identified to determine PS4 strength.
PM1
Available evidence does not show that this missense variant is in a TP53 mutational hotspot that meets PM1.
PM5
No qualifying TP53 VCEP pathogenic or likely pathogenic missense comparator variant at codon 379 was identified from the available evidence, so PM5 was not assessed.
PP1
No segregation data were identified to assess co-segregation with Li-Fraumeni syndrome-associated cancers.
PP3
Available computational evidence does not support a damaging effect under the TP53 VCEP missense rules.
PP4
No phenotype-specific low-VAF observation data were identified to assess the TP53 VCEP PP4 rules for constitutional mosaicism or related clinical context.
Benign
BA1
Population data do not meet the TP53 VCEP BA1 threshold.
BS1
Population data do not meet the TP53 VCEP BS1 threshold.
BS2
No single-source series of unaffected older female carriers was identified to assess BS2 under the TP53 VCEP framework.
BS4
No family data were identified showing lack of segregation with Li-Fraumeni syndrome-associated cancers, so BS4 was not assessed.
N/A · 10
PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.95699e-06; MAF= 0.00050%, 8/1613882 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016442; MAF= 0.01644%, 1/6082 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.07234e-06; MAF= 0.00071%, 2/282792 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00641e-05; MAF= 0.00401%, 1/24960 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0005%
· 8 / 1,613,882
0 hom · FAF 0.00044%
0 hom · FAF 0.00044%
Middle Eastern 1 / 6,082 |
0.016% |
African/African American 2 / 74,876 |
0.0027% |
South Asian 2 / 91,084 |
0.0022% |
Admixed American 1 / 59,974 |
0.0017% |
European (non-Finnish) 2 / 1,179,968 |
0.00017% |
+ 5 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.00071%
· 2 / 282,792
0 hom
0 hom
African/African American 1 / 24,960 |
0.004% |
Admixed American 1 / 35,440 |
0.0028% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.338. BayesDel score = -0.0720003.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52708100, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Understanding the function-structure and function-mutation relationships of p53
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links