NM_000546.6:c.610G>T

TP53 · NP_000537.3:p.(Glu204Ter) · NM_000546.6

GRCh37: chr17:7578239 C>A · GRCh38: chr17:7674921 C>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.(Glu204Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000546.6:c.610G>T (p.Glu204Ter) is a nonsense variant in exon 6 of TP53, producing a premature termination codon at position 204 that is predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the TP53 VCEP PVS1 flowchart.

The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting PM2 at supporting strength under the VCEP threshold of <0.00003.

The variant has been observed as a recurrent somatic mutation in COSMIC (n=100, COSV52679869) and is classified as Pathogenic by two clinical laboratories in ClinVar (ClinVarID 977783), consistent with a deleterious truncating effect.

No proband phenotype data, segregation information, de novo observations, or VAF data are available to support PS2, PS4, PP1, or PP4 scoring under the VCEP point-based system.

The VCEP functional (PS3/BS3) and in silico (PP3/BP4/BP7) criteria are limited to missense variants, in-frame deletions, synonymous variants, and intronic variants by the framework specifications and do not apply to nonsense variants. The truncating consequence is fully captured by PVS1.

Under the Tavtigian point-based classification system used by the TP53 VCEP, PVS1 (very strong = 8 points) plus PM2 (supporting = 1 point) yields a total of 9 points, which falls in the Likely Pathogenic range (6-9 points).

Final determination: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework yields a total score of 9, which maps to Likely Pathogenic under the specified Tavtigian-style ranges.

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	NM_000546.6:c.610G>T is a nonsense variant producing a premature termination codon at p.Glu204Ter. The PTC is upstream of p.Lys351 (codon 351) and is located in exon 6, not in exon 11 or the 3'-most 50 nucleotides of exon 10, and is therefore predicted to undergo nonsense-mediated decay. Per the TP53 VCEP PVS1 flowchart (Figure 1, version 2.4), nonsense variants upstream of p.Lys351 predicted to undergo NMD are assigned PVS1 at very strong strength.	vcep_pvs1_flowchart cspec pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires a different nucleotide change producing the same amino acid alteration that has been previously classified as pathogenic per TP53 VCEP specifications. The variant c.610G>T produces a stop codon (p.Glu204Ter); no alternative nucleotide change resulting in the same nonsense codon (e.g., c.610G>A also yielding E204*) has been identified as a VCEP-classified pathogenic comparator in the case materials.	cspec
PS2	Not met	No de novo observation data are available for this variant. The VCEP PS2 point-based scoring system (strongly associated LFS cancers = 4 points, moderately associated = 2 points per proband) cannot be applied without proband phenotype and parental testing data.	cspec vcep_table_of_lfs_cancers_and_points_for_ps2_and_pp1_code_application
PS3	N/A	The TP53 VCEP functional rules (PS3/BS3) are explicitly limited to missense variants and small in-frame deletions per the VCEP index and flowchart. The variant NM_000546.6:c.610G>T is a nonsense (stop-gain) variant and is not covered by the VCEP functional assay framework. The Functional-worksheet.xlsx (Supplementary Table S3) tabulates PS3/BS3 assignments for amino acid substitutions only and does not include nonsense entries (E204* is absent). The truncating consequence of this variant is already captured by PVS1.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet cspec
PS4	Not met	The VCEP PS4 point-based scoring system requires proband-level cancer phenotype data (strongly associated LFS cancers = 4 points, moderately associated = 2 points per proband). No proband phenotype data are available in the case materials to assign PS4 points. The variant has been observed as a somatic mutation in COSMIC (n=100) and is reported as Pathogenic by two clinical laboratories in ClinVar, but these do not constitute proband-level data for VCEP PS4 scoring.	cspec clinvar vcep_ps4_points_table
PS5	N/A	PS5 (same nucleotide change as a previously established pathogenic variant) is not defined in the TP53 VCEP version 2.4 criteria set. The VCEP framework does not include PS5 as an applicable criterion.	cspec
PM1	Not met	The TP53 VCEP PM1 rules are explicitly limited to missense variants: (1) missense variants within codons 175, 245, 248, 249, 273, or 282 (moderate), or (2) missense variants at cancerhotspots.org with ≥10 somatic occurrences for the same amino acid change (moderate) or 2-9 occurrences (supporting). NM_000546.6:c.610G>T is a nonsense variant at codon 204, which is not among the VCEP-designated PM1 codons. The cancerhotspots.org analysis confirms this variant does not lie in a statistically significant hotspot.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), yielding an allele frequency of 0. This is below the VCEP PM2_Supporting threshold of <0.00003 (0.003%). No single genetic ancestry group has multiple alleles with frequency >0.00004.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	N/A	The TP53 VCEP PM5 rules are explicitly limited to missense variants at an amino acid residue where a different missense variant has been previously determined to be pathogenic or likely pathogenic per VCEP specifications. NM_000546.6:c.610G>T is a nonsense variant, not a missense variant, and is therefore outside the scope of PM5 per the VCEP framework. This was confirmed by pm5_candidates.json which returned not_applicable.	cspec pm5_candidates
PM6	N/A	The TP53 VCEP declares PM6 Not Applicable. The VCEP applicability field for PM6 is 'Not applicable' and the criterion is not for use under this gene-specific framework.	cspec
PP1	Not met	No cosegregation data are available for this variant. The VCEP PP1 scoring system requires observed cosegregation in ≥3 meioses (supporting), 5-6 meioses (moderate), or ≥7 meioses (strong) across one or more families. No family studies or segregation analyses were found in the case materials.	cspec
PP2	N/A	The TP53 VCEP declares PP2 Not Applicable. The VCEP applicability field for PP2 is 'Not applicable' and the criterion is not for use under this gene-specific framework.	cspec
PP3	N/A	The TP53 VCEP PP3 rules are limited to missense variants (aGVGD class + BayesDel score criteria), single amino acid in-frame deletions (BayesDel score), and exonic/intronic splice variants (SpliceAI ≥0.2). The variant c.610G>T is a nonsense (stop-gain) variant and is not covered by any VCEP PP3 rule category. The PP3-BP4-codes.xlsx (Supplementary Table S2) is explicitly a table for missense variant bioinformatic assignments and does not include nonsense entries. SpliceAI predicts no splicing impact (max delta = 0.00).	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 vcep_pp3_bp4_codes spliceai
PP4	Not met	The VCEP PP4 criterion requires observation of the variant with a variant allele fraction (VAF) of 5-35% (supporting) or at least 2 independent observations with VAF 5-25% (moderate) to address potential clonal hematopoiesis/somatic mosaicism. No VAF data or phenotype information for individual probands are available in the case materials.	cspec
PP5	N/A	The TP53 VCEP declares PP5 Not Applicable. The VCEP explicitly states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Not met	The VCEP BA1 rule requires a filtering allele frequency (FAF) ≥0.001 (0.1%) in a single continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. The variant is absent from all gnomAD populations (AF = 0); it does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The VCEP BS1 rule requires a filtering allele frequency (FAF) ≥0.0003 (0.03%) but <0.001 in a single continental subpopulation with ≥2,000 alleles tested and ≥2 alleles present. The variant is absent from gnomAD (AF = 0); it does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	The VCEP BS2 rule requires ≥2 unrelated females who have reached at least 60 years of age without cancer (supporting), 4-7 (moderate), or ≥8 (strong), all from a single source. No such data are available in the case materials.	cspec
BS3	N/A	The TP53 VCEP BS3 functional rules are explicitly limited to missense variants and small in-frame deletions per the VCEP index and functional flowchart. The variant c.610G>T is a nonsense (stop-gain) variant and is not covered by the VCEP functional assay framework. The Functional-worksheet.xlsx does not include entries for nonsense variants at this position.	vcep_flowchart_for_application_of_functional_rule_codes vcep_functional_worksheet cspec
BS4	Not met	The VCEP BS4 rule requires lack of segregation in affected family members diagnosed with LFS-associated cancers. No family segregation data are available for this variant.	cspec
BP1	N/A	The TP53 VCEP declares BP1 Not Applicable. The VCEP applicability field for BP1 is 'Not applicable' and the criterion is not for use under this gene-specific framework.	cspec
BP2	N/A	The TP53 VCEP declares BP2 Not Applicable. The VCEP applicability field for BP2 is 'Not applicable' and the criterion is not for use under this gene-specific framework.	cspec
BP4	N/A	The TP53 VCEP BP4 rules are limited to missense variants (BayesDel score and aGVGD class criteria), synonymous variants, intronic variants, and single amino acid in-frame deletions. The variant c.610G>T is a nonsense (stop-gain) variant and falls outside all VCEP BP4 rule categories. SpliceAI predicts no splicing impact (max delta = 0.00).	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7 spliceai
BP5	N/A	The TP53 VCEP declares BP5 Not Applicable. The VCEP applicability field for BP5 is 'Not applicable' and the criterion is not for use under this gene-specific framework.	cspec
BP6	N/A	The TP53 VCEP declares BP6 Not Applicable. The VCEP explicitly states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	The VCEP BP7 rules are limited to synonymous (silent) variants and intronic variants. The variant c.610G>T is a nonsense (stop-gain) substitution that changes a glutamate codon to a stop codon, and is not a synonymous or intronic variant.	cspec vcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7
BP3	N/A	In-frame deletion/insertion in a repetitive region without known function; variant is a single nucleotide substitution, not an in-frame indel.
PM3	N/A	Recessive disorder criterion for trans configuration; TP53/Li-Fraumeni syndrome is autosomal dominant.
PM4	N/A	Protein length change due to in-frame deletion/insertion; variant is a single nucleotide substitution producing a premature stop codon.

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