Back
LYFE SCIENCES
Project: HERA
NM_000546.6:c.1123C>A
p.Gln375Lys  ·  TP53
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.339. BayesDel score = -0.143957.
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ375
Hotspots ↗