NM_000546.5:c.74+11C>T

TP53 · NP_000537.3:p.? · NM_000546.5

GRCh37: chr17:7579828 G>A · GRCh38: chr17:7676510 G>A

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity below the TP53 VCEP PM2_Supporting threshold of 0.00003.

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.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework yields a total score of -1, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. SpliceAI predicts no meaningful splice effect (max delta score 0.01), and no TP53 RNA-based PVS1 assignment was identified for this variant, so available evidence does not support applying PVS1.	cspec spliceai pvs1_gene_context pvs1_variant_assessment vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	N/A	PS1 is a same-amino-acid-change rule for variants with an established protein substitution. This intronic variant has no defined amino acid substitution, so PS1 is not applicable.	cspec
PS2	Not assessed	No confirmed de novo occurrence with the phenotype and parental testing details required for TP53 PS2 assessment was identified.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not assessed	No functional study was identified showing that this exact intronic variant causes an abnormal TP53 transcript or other validated damaging functional effect. The TP53 VCEP protein-function worksheets are directed to missense and small in-frame deletion variants and do not provide a direct PS3 assignment for this variant.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not assessed	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.	cspec gnomad_v2 gnomad_v4 vcep_ps4_points_table
PM1	N/A	PM1 in the TP53 VCEP framework is directed to missense variants at hotspot codons or recurrent somatic amino acid changes. This intronic variant does not create a defined amino acid substitution, so PM1 is not applicable.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not used in the TP53 VCEP framework.	cspec
PM4	N/A	PM4 is not used in the TP53 VCEP framework.	cspec
PM5	N/A	PM5 in the TP53 VCEP framework is a same-residue missense rule. This intronic variant is not missense-like and has no amino acid residue context for comparator review, so PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	PM6 is not used in the TP53 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified, so there is no evidence to support TP53 PP1.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	PP2 is not used in the TP53 VCEP framework.	cspec
PP3	Not met	This intronic +11 variant does not meet the TP53 VCEP PP3 splice threshold. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the PP3 threshold of >=0.2.	cspec spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes
PP4	Not assessed	No blood variant allele fraction data or other TP53-specific clinical observation data were identified to support PP4.	cspec
PP5	N/A	PP5 is not used in the TP53 VCEP framework.	cspec
BA1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No source was identified showing this variant in the number of unrelated older females without cancer required for TP53 BS2.	cspec
BS3	Not assessed	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.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	No lack-of-segregation evidence was identified in affected relatives with TP53-associated cancers, so BS4 cannot be assessed.	cspec
BP1	N/A	BP1 is not used in the TP53 VCEP framework.	cspec
BP2	N/A	BP2 is not used in the TP53 VCEP framework.	cspec
BP3	N/A	BP3 is not used in the TP53 VCEP framework.	cspec
BP4	Met	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.	cspec spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	BP5 is not used in the TP53 VCEP framework.	cspec
BP6	N/A	BP6 is not used in the TP53 VCEP framework.	cspec
BP7	Met	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.	cspec spliceai vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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