Final classification

Likely Benign

PM2BS3

TP53

c.1123C>A

p.Gln375Lys

This variant

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.

Transcript

NM_000546.6

HGVS · transcript:coding

NM_000546.6:c.1123C>A

GRCh38

chr17:7669668 G>T

GRCh37

chr17:7572986 G>T

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

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

PM2 + BS3 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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 ↗

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_000546.6 · variants mapped to exon structure

TP53 NM_000546.6

Fetching transcript structure from UCSC…

Applied criteria · 2 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2 threshold of less than 0.00003 overall and supports PM2 at supporting strength.

Absent from gnomAD v2.1Absent from gnomAD v4.1TP53 PM2 threshold: AF < 0.00003

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BS3 strong review Benign

In the TP53 VCEP functional worksheet, p.(Gln375Lys) is listed as Functional on Kato-class data and noLOF on Giacomelli-class data, with a pre-assigned BS3 code. These results support retained TP53 function and argue against a damaging effect.

Functional worksheet row: Q375K | Functional | noLOF | BS3TP53 VCEP BS3 applies when Kato data are functional and the majority of eligible assays do not show LOF

cspec ↗

Assessed · not applied · 5 not met · 9 not assessed

Pathogenic

PS1 No evidence was identified showing that this nucleotide change creates the same amino acid substitution as a different TP53 variant already classified as pathogenic or likely pathogenic under TP53 VCEP specifications.

PS2 No de novo observations, parental testing results, or phenotype point assignments were identified for this variant, so PS2 cannot be applied.

PS3 Available TP53 functional evidence does not support a damaging loss-of-function effect for this variant.

PS4 Although the variant is absent from gnomAD and therefore meets the population prerequisite for TP53 PS4 review, no qualifying proband observations or Li-Fraumeni syndrome point total were identified to support PS4.

PM1 This missense variant has been reported 4 times in COSMIC, but no Cancer Hotspots residue row or statistically significant hotspot evidence was identified for codon 375.

PM5 This is a missense variant at codon 375, and TP53 uses classic same-residue PM5 logic.

PP1 No segregation data, meiosis counts, or multiple affected family observations were identified for this variant, so PP1 cannot be applied.

PP3 Available computational evidence does not support confident PP3 application.

PP4 No low-variant-allele-fraction blood finding, constitutional mosaicism evidence, or other TP53-specific PP4 qualifying observation was identified, so PP4 cannot be applied.

Benign

BA1 This variant is absent from gnomAD and does not reach the TP53 BA1 filtering allele frequency threshold of 0.001.

BS1 This variant is absent from gnomAD and does not reach the TP53 BS1 filtering allele frequency threshold of 0.0003.

BS2 No source identified 2 or more unrelated older female carriers without cancer, so BS2 cannot be applied.

BS4 No family data showing lack of segregation with Li-Fraumeni syndrome-associated cancers were identified, so BS4 cannot be applied.

BP4 Computational evidence suggests a benign missense effect by BayesDel (-0.143957), and the TP53 PP3/BP4 worksheet preliminarily assigns BP4_moderate for c.1123C>A.

N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).

ClinVar ↗

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 ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

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

PMID 12826609 ↗

Found