Classification rationale

PM2 BP4BP7 VUS

TP53 c.74+11C>T

The TP53 c.74+11C>T (NP_000537.3:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold of 0.00003.² SpliceAI predicts no significant splice effect with a maximum delta score of 0.01; for a TP53 intronic variant at +11, this supports BP4_Supporting and BP7_Supporting and does not support PP3 or PVS1.³

PM2 + BP4 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7pvs1_variant_assessment

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 · 3 applied · 12 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 · 3

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_Supporting threshold of <0.00003 overall allele frequency and supports rarity.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

This intronic variant is outside the canonical +/-1,2 splice positions and lies at +11. SpliceAI predicts no splice impact with a maximum delta score of 0.01, which is at or below the TP53 VCEP BP4 threshold of <=0.1 for silent or intronic variants, supporting BP4.

Intronic position +11.SpliceAI max delta score is 0.01.

cspec ↗spliceai ↗

BP7 supporting review Benign

This intronic variant is at c.74+11, which is within the TP53 VCEP BP7 intronic range of +7 to +21 away from the splice junction, and SpliceAI predicts no impact to splicing with a maximum delta score of 0.01. This meets TP53 BP7_Supporting.

Intronic position +11.SpliceAI max delta score is 0.01.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 8 not assessed

Pathogenic

PVS1 This intronic variant is at c.74+11, outside the canonical +/-1,2 splice positions and outside the default null-variant categories used for PVS1.

PS2 No confirmed de novo occurrence with the phenotype and parental testing details required for TP53 PS2 assessment was identified.

PS3 No functional study was identified showing that this exact intronic variant causes an abnormal TP53 transcript or other validated damaging functional effect.

PS4 This variant is absent from population databases, which is compatible with the PM2_Supporting prerequisite, but no affected case series or point-based TP53 PS4 evidence was identified.

PP1 No segregation data were identified, so there is no evidence to support TP53 PP1.

PP3 This intronic +11 variant does not meet the TP53 VCEP PP3 splice threshold.

PP4 No blood variant allele fraction data or other TP53-specific clinical observation data were identified to support PP4.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the TP53 BA1 stand-alone benign threshold of filtering allele frequency >=0.001.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and does not meet the TP53 BS1 threshold of filtering allele frequency >=0.0003.

BS2 No source was identified showing this variant in the number of unrelated older females without cancer required for TP53 BS2.

BS3 No RNA or other functional study was identified showing that this exact variant has no effect on TP53 splicing or function, so BS3 cannot be applied.

BS4 No lack-of-segregation evidence was identified in affected relatives with TP53-associated cancers, so BS4 cannot be assessed.

N/A · 13 PS1 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6

Research & evidence

Population frequency

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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