The TP53 c.1123C>A (p.Gln375Lys) variant has been observed in somatic cancers in COSMIC (4 occurrences) and has been reported in ClinVar as Likely benign by a single clinical laboratory.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports TP53 PM2 at supporting strength and does not support BA1 or BS1.2 In the TP53 VCEP functional worksheet, p.(Gln375Lys) is classified as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code, supporting retained TP53 function.3 Computational evidence is mixed: REVEL is 0.339 and BayesDel is -0.143957, the TP53 PP3/BP4 worksheet preliminarily lists BP4_moderate for c.1123C>A, but that worksheet also flags possible splice impact while the case-specific SpliceAI lookup reported a max delta score of 0.00, so PP3 and BP4 were not applied pending review of the discordant splice predictions.4
TP53
Final classification
Likely Benign
TP53 c.1123C>A · p.Gln375Lys
TP53
The TP53 c.1123C>A (p.Gln375Lys) variant has been observed in somatic cancers in COSMIC (4 occurrences) and has been reported in ClinVar as Likely benign by a single clinical laboratory.
TP53 VCEP v2.4.0 Tavtigian point-based final-classification framework from CSPEC/VCEP. Applied points: BS3_Strong = -4 and PM2_Supporting = +1, for a net score of -3; Likely Benign corresponds to -6 to -2.
Classification rationale
PM2
BS3
Likely Benign
TP53 c.1123C>A
PM2 + BS3
→
Likely Benign
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codescspec ↗
4
revelbayesdelspliceai ↗vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7cspec ↗
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 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
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.339. BayesDel score = -0.143957.
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; COSV52716070, n = 4 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
5papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID 12826609
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID 16007150
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID 29979965
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID 30224644
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID 39774325
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links