Variant classification summary

NM_000546.6:c.919+17A>G

TP53 · NP_000537.3:p.? · NM_000546.6

GRCh37: chr17:7577002 T>C · GRCh38: chr17:7673684 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.?

gnomAD AF

1.8585564220558607e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 allele frequency 1.86e-06 (3/1,614,156 alleles), well below the <0.003% threshold.

2

Overall classification: VUS - PM2_Supporting (+1) is the only met criterion, and a total score of 1 falls within Rule 3 (-1 to 5) of the TP53 VCEP v2.4 framework.

Final determination: ClinGen TP53 VCEP v2.4 point-based combination rule: PM2_Supporting contributes +1 point; a total score of 1 lies within Rule3 (>= -1 and <= 5), yielding Uncertain Significance (VUS).

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	Not met: this intronic substitution at +17 has no predicted protein change and lies outside the canonical splice sites, so it is not a null variant.	cspec vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet pvs1_gene_context pvs1_variant_assessment spliceai pvs1_generic_framework PMID:25741868
PS1	N/A	Not applicable: the rule requires the same amino acid change as a known pathogenic variant, and this variant has no amino acid change (p.?).	cspec
PS2	Not assessed	Not assessed: no proband phenotype, parental testing, or maternity/paternity confirmation is available to establish a de novo event.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	N/A	Not applicable: PS3 requires functional assay results for a specific amino acid change, and this intronic variant has no protein consequence (p.?).	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet spliceai PMID:25741868
PS4	Not assessed	Not assessed: no proband phenotype or case-control data exists to tally PS4 points.	cspec vcep_ps4_points_table
PM1	N/A	Not applicable: PM1 applies only to missense variants, and this intronic variant alters no codon (p.?).	cspec
PM2	Met	Met (supporting): gnomAD v4.1 allele frequency 1.86e-06 (3/1,614,156 alleles), well below the <0.003% PM2 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP excludes PM3, and Li-Fraumeni syndrome is autosomal dominant, not recessive.	cspec
PM4	N/A	Not applicable: no in-frame insertion/deletion or stop-loss is produced; the protein is unchanged (p.?).	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a residue with known pathogenic variants; this variant is intronic (p.?).	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP has dropped PM6, using PS2 exclusively for all de novo evidence.	cspec
PP1	Not assessed	Not assessed: no family segregation studies or meiosis counts are available.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP excludes PP2, and the variant is intronic, not missense.	cspec
PP3	Not assessed	Not assessed: no SpliceAI score was available to test the required >=0.2 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.	cspec spliceai vcep_pp3_bp4_codes vcep_pvs1_splicing_worksheet
PP4	Not assessed	Not assessed: no multigene-panel variant allele fraction (VAF 5-35%) observation is available for this variant.	cspec
PP5	N/A	Not applicable: no ClinVar expert-panel classification exists for this exact variant.	cspec clinvar
BA1	Not met	Not met: highest eligible group frequency ~1.7e-06, about 600-fold below the >=0.1% BA1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: highest eligible group frequency 1.7e-06, about 180-fold below the >=0.03% BS1 threshold.	cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: no source provides counts of unaffected women aged 60 or older without cancer.	cspec
BS3	N/A	Not applicable: BS3 requires functional assay data for the specific amino acid change, and none exists for this intronic variant.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet spliceai PMID:25741868
BS4	Not assessed	Not assessed: no family testing data exists to demonstrate lack of segregation in affected relatives.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP excludes BP1 because missense variants are a major disease mechanism in TP53.	cspec
BP2	N/A	Not applicable: the TP53 VCEP excludes BP2, and no trans/cis observation with a pathogenic variant is documented.	cspec clinvar
BP3	N/A	Not applicable: no in-frame indel in a repetitive region; the variant is a single intronic substitution.	cspec
BP4	Not assessed	Not assessed: no SpliceAI score was available to test the required <=0.1 threshold. Flagged for human review: the SpliceAI score has not yet been obtained.	cspec spliceai vcep_pp3_bp4_codes
BP5	N/A	Not applicable: the TP53 VCEP excludes BP5, and no alternate molecular basis of disease is documented.	cspec
BP6	N/A	Not applicable: no ClinVar expert-panel benign classification exists; the Likely benign label comes only from routine laboratory submissions.	cspec clinvar
BP7	Not assessed	Not assessed: no SpliceAI score to confirm the <=0.1 requirement, and no RNA assay data are available. Flagged for human review: the SpliceAI score has not yet been obtained.	cspec spliceai

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