NM_000546.6:c.-89A>G

TP53 · NP_000537.3:p.? · NM_000546.6

GRCh37: chr17:7590755 T>C · GRCh38: chr17:7687437 T>C

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.?

gnomAD AF

5.518210093307916e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

All three requested criteria are not applicable because NM_000546.6:c.-89A>G is a 5′-UTR single-nucleotide variant with p.? and no qualifying protein-length or null-variant consequence.

The governing TP53 VCEP PVS1 files were searched for c.-89A>G and the requested p.? notations; no exact pre-assigned entry was found.

The ClinGen TP53 VCEP v2.4 framework governs all four requested criteria.

PS2, PP1, and BS4 cannot be assessed because the case contains no proband, parental, pedigree, relative-genotype, phenotype, or meiosis evidence.

PM6 is not applicable because the TP53 VCEP explicitly dropped PM6 and directs de novo evidence to PS2.

The governing Table-of-LFS-Cancers-and-Points-for-PS2-and-PP1-Code-Application.pdf was searched under c.-89A>G, c.89A>G, p.Asn30Ser, and p.?; no variant-specific entry was found.

All three requested computational criteria are not_applicable because NM_000546.6:c.-89A>G is a 5' UTR variant with protein consequence p.?, not a missense, synonymous, intronic, or splice-region variant within the applicable TP53 VCEP rules.

The ClinGen TP53 VCEP v2.4 framework governs all four requested criteria.

Population frequency evidence does not meet BA1, BS1, or PM2 because the relevant gnomAD v4.1 frequencies exceed the TP53 PM2 limit but remain below the TP53 BS1 and BA1 limits.

BS2 is not assessable because no individual-level unaffected older female carrier data are available.

Final determination: Under the ClinGen TP53 VCEP v2.4 point-based rules, a total score from -1 through 5 maps to VUS; this assessment has 0 points because no criterion is applied.

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	N/A	Not applicable: c.-89A>G is a 5′-UTR p.? variant, and SpliceAI max delta 0.072 does not indicate a qualifying splice-loss null consequence.	cspec spliceai vcep_pvs1_flowchart vcep_pvs1_splicing_worksheet
PS1	N/A	Not applicable: c.-89A>G has protein consequence p.? rather than a missense amino-acid substitution required for same-residue PS1.	cspec
PS2	Not assessed	Not assessed: no proband phenotype or confirmed maternity-and-paternity de novo observation is available to calculate the TP53 VCEP PS2 points.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	N/A	Not applicable: the VCEP functional framework covers missense variants and small in-frame deletions, whereas c.-89A>G is an upstream noncoding substitution with p.?.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not assessed	Not assessed: no proband phenotype, tumor pathology, or PS4 point total is available to compare with the 1-point Supporting threshold.	cspec vcep_ps4_points_table
PM1	N/A	Not applicable: c.-89A>G has no encoded residue, so it cannot be assessed against TP53 PM1 hotspot codons or a functional domain.	cspec
PM2	Not met	Not met: gnomAD v4.1 total AF is 0.0000551821, above the TP53 VCEP PM2 limit of 0.00003.	cspec gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates PM3 as Not Applicable.	cspec
PM4	N/A	Not applicable: the single-nucleotide 5′-UTR variant has p.? and causes no documented protein length change.	cspec
PM5	N/A	Not applicable: c.-89A>G has protein consequence p.? and is not a missense variant eligible for same-residue PM5 comparison.	cspec
PM6	N/A	Not applicable: the TP53 VCEP v2.4 explicitly drops PM6 and directs all de novo evidence to the PS2 framework.	cspec
PP1	Not assessed	Not assessed: no informative relatives or meioses are available to compare variant carriage with LFS-associated cancer status.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP marks PP2 not applicable, and c.-89A>G has no missense protein consequence.	cspec
PP3	N/A	Not applicable: c.-89A>G is a 5' UTR variant with p.?, outside PP3's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1 spliceai
PP4	Not assessed	Not assessed: no multigene-panel VAF observation is available to compare with the TP53 PP4 5-35% Supporting range.	cspec
PP5	N/A	Not applicable: the TP53 VCEP excludes PP5, and ClinVar has no exact-variant expert-panel classification.	cspec clinvar
BA1	Not met	Not met: the highest eligible non-founder gnomAD v4.1 FAF is 0.000084030, below the TP53 VCEP BA1 threshold of 0.001.	cspec gnomad_v4
BS1	Not met	Not met: the highest eligible non-founder gnomAD v4.1 FAF is 0.000084030, below the TP53 VCEP BS1 lower threshold of 0.0003.	cspec gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no source provides the required count of unrelated female carriers aged at least 60 years without cancer.	cspec gnomad_v4
BS3	N/A	Not applicable: the VCEP functional framework covers missense variants and small in-frame deletions, whereas c.-89A>G is an upstream noncoding substitution with p.?.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no affected family members with documented non-carriage of the variant are available for the TP53 VCEP BS4 Strong rule.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP marks BP1 not applicable, and c.-89A>G is not a missense variant with a defined residue.	cspec
BP2	N/A	Not applicable: the TP53 VCEP version 2.4 explicitly designates BP2 as Not Applicable.	cspec
BP3	N/A	Not applicable: c.-89A>G is a 5′-UTR single-nucleotide substitution, not an in-frame deletion in a repetitive protein region.	cspec
BP4	N/A	Not applicable: c.-89A>G is a 5' UTR variant with p.?, outside BP4's missense and intronic/splice-region scope; SpliceAI 0.072 is therefore not evaluated.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1 spliceai
BP5	N/A	Not applicable: the TP53 VCEP excludes BP5 and provides no governing alternate-molecular-basis rule for this case.	cspec
BP6	N/A	Not applicable: the TP53 VCEP excludes BP6, and ClinVar has no exact-variant expert-panel benign classification.	cspec clinvar
BP7	N/A	Not applicable: c.-89A>G is a 5' UTR variant with p.?, not synonymous; BP7 therefore does not apply regardless of the SpliceAI max delta 0.072.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1 spliceai

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.