Variant classification summary

NM_000546.5:c.672+6G>A

TP53 · NP_000537.3:p.? · NM_000546.5

GRCh37: chr17:7578171 C>T · GRCh38: chr17:7674853 C>T

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.?

gnomAD AF

1.858782125951077e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): gnomAD v4.1 total allele frequency is 1.86e-06 (3/1,613,960 alleles), well below the 0.00003 VCEP rarity ceiling.

2

With PM2_Supporting the only met criterion (+1 point), total score 1 falls in Rule3's -1 to 5 range, yielding a final classification of Uncertain Significance.

Final determination: Under the ClinGen TP53 VCEP v2.4 point-based (Tavtigian) framework, PM2_Supporting (+1 point) is the only applied criterion, giving a total score of 1, which falls in the Rule3 range of -1 to 5 and therefore maps to Uncertain Significance.

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 assessed	Not assessed: insufficient evidence was available to determine whether this intronic +6 donor variant causes loss of function through a null mechanism.
PS1	N/A	Not applicable: this intronic splice-site variant produces no amino acid change (p.?) to compare against an established pathogenic missense.	cspec PMID:17576681
PS2	Not assessed	Not assessed: no de novo occurrence is documented, and neither ClinVar submission reports parental testing for this variant.	cspec clinvar
PS3	N/A	Not applicable: the TP53 functional assays that define PS3 apply only to missense variants, and this intronic variant has no amino acid change.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not met	Not met: no proband carrying this variant with a documented phenotype was identified, giving 0 points versus the 1-point supporting threshold.	cspec clinvar PMID:17392385 PMID:25394175
PM1	N/A	Not applicable: PM1 hotspot rules apply to missense changes at specific codons, and this intronic variant alters no amino acid (p.?).	cspec
PM2	Met	Met (Supporting): gnomAD v4.1 total allele frequency is 1.86e-06 (3/1,613,960 alleles), far below the 0.00003 VCEP ceiling.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: PM3 requires a recessive disorder, while TP53-related Li-Fraumeni syndrome is autosomal dominant.	cspec
PM4	Not assessed	Not assessed: insufficient evidence was available to evaluate a change in protein length for this intronic variant.
PM5	N/A	Not applicable: this intronic variant produces no missense change at a residue where a different pathogenic missense could be compared.	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP v2.4 drops PM6, handling all de novo evidence through PS2 instead.	cspec
PP1	Not assessed	Not assessed: no segregation data exists; no affected relatives are documented as tested for this variant.	cspec clinvar gnomad_v2 gnomad_v4
PP2	N/A	Not applicable: PP2 is removed by the TP53 VCEP and applies only to missense variants regardless.	cspec
PP3	Not assessed	Not assessed: insufficient evidence was available from in silico prediction tools to score this criterion.
PP4	Not assessed	Not assessed: no variant allele fraction (VAF) data was reported, which the TP53 VCEP PP4 rule requires.	cspec clinvar
PP5	N/A	Not applicable: PP5 is removed by the TP53 VCEP, and no expert-panel pathogenic classification of this variant exists in ClinVar.	cspec clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 ancestry frequency is 2.20e-05, over 45-fold below the 0.001 BA1 threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest gnomAD v4.1 ancestry frequency is 2.20e-05, far below the 0.0003 BS1 lower threshold.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no source documents unaffected carriers past age 60 without cancer, which BS2 requires.	cspec clinvar gnomad_v4
BS3	N/A	Not applicable: BS3 is defined by protein-function assays for missense variants, and this intronic variant has no amino acid change.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no family testing is documented to show affected relatives who do not carry the variant.	cspec clinvar
BP1	N/A	Not applicable: BP1 is removed by the TP53 VCEP and applies only to missense variants.	cspec
BP2	N/A	Not applicable: BP2 is removed by the TP53 VCEP, and no second TP53 variant or phase information exists.	cspec
BP3	Not assessed	Not assessed: insufficient evidence was available to evaluate whether this variant lies in a functionally silent repetitive region.
BP4	Not assessed	Not assessed: insufficient evidence was available from in silico splicing predictors to score this intronic variant.
BP5	N/A	Not applicable: BP5 is removed by the TP53 VCEP, so no alternate-molecular-basis evidence applies.	cspec
BP6	N/A	Not applicable: BP6 is removed by the TP53 VCEP, and no expert-panel benign classification of this variant exists in ClinVar.	cspec clinvar
BP7	Not assessed	Not assessed: no RNA splicing assay data exists, which would be required to demonstrate no splicing aberration.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.