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
TP53
Final classification
Likely Benign
TP53 c.1136G>A · p.Arg379His
TP53
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 ↗
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:12826609
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:30224644
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links