Variant classification summary

NM_000546.6:c.574C>T

TP53 · NP_000537.3:p.(Gln192Ter) · NM_000546.6

GRCh37: chr17:7578275 G>A · GRCh38: chr17:7674957 G>A

Gene: TP53 Transcript: NM_000546.6

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gln192Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: TP53 p.Gln192Ter creates a premature stop upstream of p.Lys351, meeting the VCEP nonsense-mediated-decay rule.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the TP53 VCEP rarity threshold.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 point-based framework, PVS1 very strong contributes 8 points and PM2 supporting contributes 1 point; the total of 9 points maps to Likely Pathogenic.

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	Met	Met, very strong: TP53 p.Gln192Ter creates a premature stop at codon 192, upstream of p.Lys351, meeting the VCEP NMD PVS1 rule.	cspec vcep_pvs1_flowchart
PS1	N/A	Not applicable: p.(Gln192Ter) is a nonsense variant, not an amino-acid substitution eligible for the TP53 VCEP PS1 rule.	cspec
PS2	Not assessed	Not assessed: no verified de novo observation, parental testing, or PS2 phenotype points are documented for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	Not assessed	Not assessed: TP53's functional worksheet has no p.Gln192Ter entry, and no reviewed publication reports a validated functional assay for this exact nonsense variant.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16007150 PMID:19336573 PMID:21467160
PS4	Not assessed	Not assessed: the PS4 point total is unavailable, so the VCEP thresholds of 1-1.5, 2-3.5, 4-7.5, or >=8 points cannot be applied.	cspec vcep_ps4_points_table
PM1	N/A	Not applicable: p.(Gln192Ter) is nonsense, while the TP53 VCEP PM1 rule requires a missense variant in an approved codon or hotspot.	cspec vcep_output
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed frequency 0 versus the TP53 VCEP PM2 threshold <0.00003.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the TP53 VCEP explicitly excludes PM3 for autosomal-dominant Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: p.Gln192Ter is a nonsense substitution, not an in-frame indel or other PM4-eligible protein-length change.	cspec
PM5	N/A	Not applicable: PM5 requires a missense variant, but this case is the nonsense change p.(Gln192Ter).	cspec pm5_candidates
PM6	N/A	Not applicable: the TP53 VCEP explicitly designates PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative genotypes or verified cosegregating meioses are documented for this variant.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PP2	N/A	Not applicable: the TP53 VCEP explicitly excludes PP2, and this case variant is nonsense rather than missense.	cspec
PP3	N/A	Not applicable: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP PP3 scope for missense, deletion, and splice-impact variants.	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
PP4	Not assessed	Not assessed: no qualifying TP53 VAF observation is documented, so the VCEP thresholds of 5-25% or 5-35% cannot be applied.	cspec
PP5	N/A	Not applicable: the TP53 VCEP disallows PP5, and ClinVar shows no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, not a TP53 VCEP BA1 filtering allele frequency >=0.001 in one eligible ancestry group.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, not a TP53 VCEP BS1 filtering allele frequency from 0.0003 to below 0.001.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no single-source count of at least two unrelated unaffected females aged 60 or older is available for the TP53 VCEP BS2 rule.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no exact p.Gln192Ter functional result was found in the governing TP53 worksheet or reviewed literature to demonstrate retained function.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet PMID:16007150 PMID:19336573 PMID:21467160
BS4	Not assessed	Not assessed: no affected family members with verified non-segregation or genotype results are documented.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
BP1	N/A	Not applicable: the TP53 VCEP explicitly excludes BP1, and this case variant is nonsense rather than missense.	cspec
BP2	N/A	Not applicable: the TP53 VCEP marks BP2 as not applicable despite describing trans-phase observation scenarios.	cspec
BP3	N/A	Not applicable: p.Gln192Ter is a premature-stop nonsense variant, not a benign in-frame deletion within a repetitive region.	cspec
BP4	N/A	Not applicable: p.(Gln192Ter) is a nonsense variant, outside the TP53 VCEP BP4 scope for missense, deletion, and splice-impact variants.	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
BP5	N/A	Not applicable: the TP53 VCEP explicitly marks BP5 as not applicable and supplies no governing BP5 rule.	cspec
BP6	N/A	Not applicable: the TP53 VCEP disallows BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: p.(Gln192Ter) is a nonsense variant, whereas TP53 VCEP BP7 is restricted to synonymous or intronic variants.	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

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