Variant classification summary

NM_000546.5:c.612_623del

TP53 · NP_000537.3:p.(Glu204_Asp207del) · NM_000546.5

GRCh37: chr17:7578225 GTCATCCAAATAC>G · GRCh38: chr17:7674907 GTCATCCAAATAC>G

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Glu204_Asp207del)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.5:c.612_623del (p.Glu204_Asp207del) is an in-frame deletion of 12 nucleotides in exon 6 of TP53, removing four amino acids (204-207) within the DNA-binding core domain (residues 102-292).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (0 alleles across all population databases), meeting PM2_Supporting under the TP53 VCEP (AF < 0.00003).

3

The variant is absent from ClinVar and has not been previously classified by any diagnostic laboratory or expert panel.

4

The variant is not a null variant (nonsense, frameshift, or canonical splice) and is not addressed by the TP53 VCEP PVS1 decision tree, which covers only truncating and exon-level deletion variants. PVS1 is not applicable.

5

No variant-specific functional data are available. The VCEP Functional-worksheet catalogs single amino acid substitutions and deletions but does not include the 4-amino-acid deletion p.Glu204_Asp207del. Two reviewed publications (PMID:11900253, PMID:8023157) discuss p53 structure and function at the gene level but do not mention this specific variant.

6

Several criteria (PS2, PS4, PP1, PP4, BS2, BS4) could not be assessed due to absence of proband phenotype, family, or segregation data. Multiple VCEP criteria (PM4, PM6, PP2, PP5, BP1, BP2, BP3, BP5, BP6) are explicitly marked as Not Applicable under the TP53 VCEP v2.4 framework.

7

The only applicable and met criterion is PM2_Supporting (absent from population databases). All other assessable criteria are either not applicable, not met, or not assessed due to insufficient data.

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 1, which maps to VUS 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	N/A	NM_000546.5:c.612_623del is an in-frame deletion removing 4 amino acids (p.Glu204_Asp207del) without introducing a premature termination codon. The TP53 VCEP PVS1 flowchart (v2.4) covers nonsense, frameshift, canonical splice site, and exon-level deletion variants only. In-frame deletions are not addressed by the PVS1 decision tree and do not qualify as null variants under the VCEP framework.	vcep_pvs1_flowchart pvs1_variant_assessment
PS1	Not met	No variant with the same amino acid change (p.Glu204_Asp207del) has been previously classified as pathogenic or likely pathogenic under the TP53 VCEP specifications. This variant is absent from ClinVar and no prior VCEP-classified comparator exists.	clinvar
PS2	Not assessed	No de novo observation data available. VCEP PS2 requires proband-level cancer diagnosis and confirmed parentage to assign points based on the LFS cancer scoring table. No proband or family data were provided for this case.
PS3	Not assessed	The TP53 VCEP Functional-worksheet (Supplementary Table S3) catalogs PS3/BS3 assignments for single amino acid substitutions and single amino acid deletions but does not contain an entry for the 4-amino-acid deletion p.Glu204_Asp207del. No variant-specific functional assay data were identified in the two publications reviewed (PMID:11900253, PMID:8023157), neither of which mentions this variant. OncoKB annotates this variant as Likely Oncogenic/Likely Loss-of-function, but this represents somatic curated inference rather than direct germline functional evidence qualifying for PS3 under VCEP rules.	vcep_functional_worksheet oncokb
PS4	Not assessed	VCEP PS4 uses a point-based system requiring proband-level cancer diagnoses matched to the LFS cancer scoring table. No proband phenotype data were provided. The variant is absent from ClinVar and COSMIC, providing no population-level case data.
PS5	Not met	No reputable source has reported NM_000546.5:c.612_623del as pathogenic. The variant is absent from ClinVar and no published classification from a diagnostic laboratory or expert panel was identified.	clinvar
PM1	N/A	The TP53 VCEP PM1 rule (v2.4) is restricted to missense variants at six specified hotspot codons (175, 245, 248, 249, 273, 282) for moderate strength, or missense variants with cancerhotspots.org somatic counts for supporting strength. NM_000546.5:c.612_623del is an in-frame deletion, not a missense variant. Under VCEP specifications, PM1 is not applicable to non-missense variant types.	cspec
PM2	Met	NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is below the VCEP PM2_Supporting threshold of 0.00003 (0.003%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	The TP53 VCEP (v2.4) explicitly marks PM4 as Not Applicable. This criterion is not used under the gene-specific framework.	cspec
PM5	N/A	The TP53 VCEP PM5 rule applies to missense variants at an amino acid residue where a different missense change has been classified as P/LP. NM_000546.5:c.612_623del is a 4-amino-acid in-frame deletion, not a missense substitution. The variant class does not fit the PM5 framework.	cspec pm5_candidates
PM6	N/A	The TP53 VCEP (v2.4) explicitly marks PM6 as Not Applicable; de novo evidence is assessed under PS2 using the combined PS2/PM6 point system.	cspec
PP1	Not assessed	No cosegregation data available. VCEP PP1 requires observation in 3-4 meioses for supporting, 5-6 for moderate, or ≥7 for strong across families. No family or segregation data were provided.
PP2	N/A	The TP53 VCEP (v2.4) explicitly marks PP2 as Not Applicable.	cspec
PP3	N/A	The TP53 VCEP in silico framework (PP3-BP4 flowchart and PP3-BP4-codes.xlsx) covers missense, synonymous, and intronic variants. Single amino acid in-frame deletions are addressed by the TP53-single-amino-acid-deletions-BayesDel-scores spreadsheet. This variant is a 4-amino-acid in-frame deletion, a variant type not covered by any VCEP in silico prediction framework. SpliceAI predicts no splicing impact (max delta = 0.00). No BayesDel or REVEL score is available for this multi-residue deletion.	spliceai vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
PP4	Not assessed	VCEP PP4 requires observation of the variant at low variant allele fraction (VAF 5-35%) in blood, suggestive of somatic mosaicism or clonal hematopoiesis. No VAF or phenotype data were provided for this case.
PP5	N/A	The TP53 VCEP (v2.4) explicitly marks PP5 as Not Applicable. Per the user's global PP5 rule, ClinVar 3-star expert panel classification could override this, but the variant is absent from ClinVar entirely, so no override applies.	cspec clinvar
BA1	Not met	NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is far below the VCEP BA1 stand-alone threshold of ≥0.001 (0.1%) in any continental subpopulation.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_000546.5:c.612_623del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency of 0 is below the VCEP BS1 strong threshold of ≥0.0003 (0.03%) in any continental subpopulation with ≥2,000 alleles and ≥2 variant alleles.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	VCEP BS2 requires ≥2 unrelated females aged ≥60 years without cancer (supporting) from a single source, excluding sarcoma diagnoses at ≥61 years. No such data were provided for this variant.
BS3	Not assessed	The TP53 VCEP Functional-worksheet does not contain an entry for p.Glu204_Asp207del. Single amino acid substitutions at E204 and D207 show mixed functional outcomes (BS3 for most substitutions; PS3_Moderate for E204G and D207G), but these do not represent functional data for the 4-amino-acid deletion. No variant-specific functional data were identified in the reviewed literature.	vcep_functional_worksheet
BS4	Not assessed	VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. No family or segregation data were provided.
BP1	N/A	The TP53 VCEP (v2.4) explicitly marks BP1 as Not Applicable because truncating variants account for only a portion of disease-causing variants in TP53.	cspec
BP2	N/A	The TP53 VCEP (v2.4) explicitly marks BP2 as Not Applicable.	cspec
BP3	N/A	The TP53 VCEP (v2.4) explicitly marks BP3 as Not Applicable.	cspec
BP4	N/A	The TP53 VCEP in silico framework for BP4 covers missense, synonymous, intronic, and single amino acid in-frame deletion variants. This variant is a 4-amino-acid in-frame deletion, a variant type not addressed by any VCEP in silico prediction framework. No BayesDel score is available for this multi-residue deletion.	spliceai vcep_pp3_bp4_codes vcep_tp53_single_amino_acid_deletions_bayesdel_scores_1
BP5	N/A	The TP53 VCEP (v2.4) explicitly marks BP5 as Not Applicable.	cspec
BP6	N/A	The TP53 VCEP (v2.4) explicitly marks BP6 as Not Applicable. Per the user's global BP6 rule, ClinVar 3-star expert panel benign classification could override this, but the variant is absent from ClinVar, so no override applies.	cspec clinvar
BP7	N/A	VCEP BP7 applies to synonymous (silent) or intronic variants with no predicted splicing impact. NM_000546.5:c.612_623del is an in-frame deletion, not a synonymous or intronic variant.	cspec

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