NM_000546.5:c.202G>T

TP53 · NP_000537.3:p.(Glu68Ter) · NM_000546.5

GRCh37: chr17:7579485 C>A · GRCh38: chr17:7676167 C>A

Gene: TP53 Transcript: NM_000546.5

Final call

Likely Pathogenic

PVS1 very strong

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Glu68Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 very strong: the exon 4 nonsense variant truncates TP53 at codon 68, upstream of p.Lys351, with predicted nonsense-mediated decay.

Final determination: Under the ClinGen TP53 Expert Panel Version 2.4 Tavtigian-style point framework, PVS1 very strong contributes 8 points, and scores from 6 through 9 points classify a variant as 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: TP53 VCEP full-strength PVS1 applies because the exon 4 stop at codon 68 is upstream of p.Lys351 and predicted to undergo NMD.	cspec vcep_pvs1_flowchart spliceai
PS1	N/A	Not applicable: p.(Glu68Ter) is a nonsense variant, not a missense substitution eligible for same-amino-acid PS1 comparison.	cspec
PS2	Not assessed	Not assessed: no documented de novo observation, parental testing, or eligible proband cancer-point total is available to assign the TP53 PS2 threshold.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	N/A	Not applicable: the TP53 VCEP functional rules cover missense variants and small in-frame deletions, not this nonsense p.(Glu68Ter) substitution.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
PS4	Not assessed	Not assessed: no documented proband phenotype or PS4 points, and PM2_Supporting is not established.	cspec vcep_ps4_points_table
PM1	N/A	Not applicable: p.(Glu68Ter) is a nonsense variant at codon 68, outside all six TP53 VCEP PM1 codons 175, 245, 248, 249, 273, and 282.	cspec
PM2	Not assessed	Not assessed: gnomAD frequency and ancestry-specific allele counts needed for the TP53 PM2 thresholds of <0.00003 and <0.00004 are unavailable.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: the TP53 VCEP explicitly excludes PM3 for autosomal dominant Li-Fraumeni syndrome.	cspec
PM4	N/A	Not applicable: the TP53 VCEP designates PM4 as not applicable, and this variant is a nonsense loss-of-function change.	cspec
PM5	N/A	Not applicable: p.(Glu68Ter) is a nonsense variant, whereas TP53 VCEP PM5 requires a different pathogenic or likely pathogenic missense variant at the same residue.	cspec
PM6	N/A	Not applicable: the TP53 VCEP Version 2.4 framework explicitly designates PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: no affected relatives with matching genotypes or countable informative meioses are documented for comparison with the 3-meiosis PP1 Supporting threshold.	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 this case is a nonsense rather than missense variant.	cspec
PP3	N/A	Not applicable: the variant is nonsense, while TP53 VCEP PP3 is scoped to missense or splice-impact variants, not truncating variants.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
PP4	Not assessed	Not assessed: no variant allele fraction observations are reported for comparison with the VCEP's 5-25% or 5-35% thresholds.	cspec
PP5	N/A	Not applicable: the TP53 VCEP prohibits PP5, and this exact ClinVar record has zero expert-panel submissions.	cspec clinvar
BA1	Not assessed	Not assessed: no qualifying ancestry-specific filtering allele frequency is available to compare with the TP53 VCEP BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not assessed	Not assessed: no qualifying ancestry-specific filtering allele frequency is available to compare with the TP53 VCEP BS1 range of 0.0003 to <0.001.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no single-source series of unrelated female carriers aged at least 60 years without cancer is documented for the TP53 BS2 rule.	cspec
BS3	N/A	Not applicable: the TP53 VCEP BS3 functional rules cover missense variants and small in-frame deletions, not this nonsense p.(Glu68Ter) substitution.	cspec vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet
BS4	Not assessed	Not assessed: no affected family members with LFS-associated cancer and documented variant testing are available to demonstrate lack of segregation.	cspec
BP1	N/A	Not applicable: the TP53 VCEP marks BP1 not applicable, and p.(Glu68Ter) is a nonsense variant rather than missense.	cspec
BP2	Not assessed	Not assessed: no affected-proband observations, comparator TP53 variants, or phase data establish the VCEP's trans or three-observation BP2 rule.	cspec clinvar
BP3	N/A	Not applicable: the TP53 VCEP designates BP3 as not applicable, and this variant is a protein-truncating nonsense change.	cspec
BP4	N/A	Not applicable: the variant is nonsense, while TP53 VCEP BP4 is scoped to missense or splice-impact variants, not truncating variants.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP5	N/A	Not applicable: the TP53 VCEP explicitly excludes BP5 from use for this gene.	cspec
BP6	N/A	Not applicable: the TP53 VCEP prohibits BP6, with no benign expert-panel classification for this exact variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 is limited to synonymous or intronic variants, whereas this variant is a nonsense substitution producing p.(Glu68Ter).	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7

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