Variant classification summary

NM_000546.6:c.431_436del

TP53 · NP_000537.3:p.(Gln144_Trp146delinsArg) · NM_000546.6

GRCh37: chr17:7578493 CACAGCT>C · GRCh38: chr17:7675175 CACAGCT>C

Gene: TP53 Transcript: NM_000546.6

Final call

VUS

PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.6

Protein

NP_000537.3:p.(Gln144_Trp146delinsArg)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.6:c.431_436del (p.Gln144_Trp146delinsArg) is a 6-bp in-frame deletion in exon 5 of TP53, removing two amino acids (Q144 and W146) in the DNA-binding core domain L2 loop region and inserting arginine.

2

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2_Supporting (allele frequency < 0.003%).

3

The variant has not been reported in ClinVar and has not been observed in COSMIC.

4

SpliceAI predicts no splicing impact (max delta score = 0.00).

5

The variant is not covered by the VCEP PVS1 framework (in-frame deletion, not a null variant), nor by VCEP PP3/BP4 in silico rules (multi-amino-acid deletion, not a missense or single-AA deletion).

6

No variant-specific functional assay data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) are available; the VCEP Functional worksheet does not contain this variant. OncoKB infers a Likely Loss-of-function but this is a somatic curation and not a direct germline functional assay.

7

No proband data, segregation data, de novo observations, or cancer-phenotype data were available for this variant.

8

Only one criterion met: PM2_Supporting. All other applicable criteria are either not met, not assessed due to absent data, or not applicable per VCEP specifications.

Final determination: Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 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_000546.6:c.431_436del is a 6-bp in-frame deletion resulting in p.(Gln144_Trp146delinsArg). The TP53 VCEP PVS1 flowchart applies exclusively to null variants (nonsense, frameshift, canonical splice, initiation codon, CNVs). In-frame deletions are not covered by the PVS1 decision tree.	vcep_pvs1_flowchart
PS1	Not met	VCEP PS1 requires a same-residue missense variant previously classified as pathogenic or likely pathogenic by TP53 VCEP specifications. No comparator variant at residues 144-146 was identified with a VCEP classification.
PS2	Not assessed	No de novo observation data available for this variant. VCEP PS2 point-based scoring requires proband-level cancer data.
PS3	Not assessed	This 2-amino-acid in-frame deletion (p.Gln144_Trp146delinsArg) is not listed in the VCEP Functional worksheet (Supplementary Table S3), which covers single amino acid substitutions and single amino acid deletions. No variant-specific functional assay data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) was identified for this specific variant. OncoKB annotation of Likely Loss-of-function is a curated inference, not direct functional assay data.	vcep_functional_worksheet oncokb
PS4	Not assessed	No proband data available. The variant is absent from ClinVar. VCEP PS4 point-based scoring requires proband-level cancer phenotype data.	clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and no variant-specific publications were identified.	clinvar
PM1	N/A	VCEP PM1 applies to missense variants at codons 175, 245, 248, 249, 273, 282, or germline missense variants with ≥2 somatic occurrences for the same amino acid change at cancerhotspots.org. This variant is an in-frame deletion, not a missense substitution.
PM2	Met	NM_000546.6:c.431_436del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This satisfies the VCEP PM2_Supporting rule requiring an allele frequency below 0.00003 (0.003%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	VCEP TP53 specifications mark PM4 as Not Applicable for this gene.
PM5	N/A	VCEP PM5 applies to missense variants at the same amino acid residue where another missense variant has been classified as pathogenic or likely pathogenic. The assessed variant is an in-frame deletion (not a missense change), and the pm5_candidates analysis confirmed it is not eligible for classic same-residue missense PM5.	pm5_candidates
PM6	N/A	VCEP TP53 specifications mark PM6 as Not Applicable for this gene.
PP1	Not assessed	No cosegregation data available. VCEP PP1 requires observation of cosegregation in 3 or more meioses across families.
PP2	N/A	VCEP TP53 specifications mark PP2 as Not Applicable for this gene.
PP3	Not met	This variant is a 2-amino-acid in-frame deletion, which is not covered by the VCEP PP3 rules. VCEP PP3 addresses missense variants (requiring aGVGD and BayesDel thresholds), single amino acid in-frame deletions (requiring BayesDel ≥ 0.16), and exonic/intronic variants with predicted splice effects (SpliceAI ≥ 0.2). SpliceAI max delta score is 0.00. No BayesDel score is available for this multi-AA deletion type.	spliceai vcep_pp3_bp4_codes
PP4	Not assessed	VCEP PP4 requires observation of the variant with a variant allele fraction (VAF) of 5-35%. No VAF data or phenotype data are available for this variant.
PP5	N/A	VCEP TP53 specifications mark PP5 as Not Applicable; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	VCEP BA1 requires a filtering allele frequency ≥ 0.001 (0.1%) in a gnomAD continental subpopulation. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4
BS1	Not met	VCEP BS1 requires a filtering allele frequency ≥ 0.0003 (0.03%) but < 0.001 in a gnomAD continental subpopulation. The variant is absent from all gnomAD populations.	gnomad_v2 gnomad_v4
BS2	Not assessed	VCEP BS2 requires observation of the variant in unrelated females who have reached at least 60 years of age without cancer. No such data are available.
BS3	Not assessed	This 2-amino-acid in-frame deletion is not listed in the VCEP Functional worksheet. No variant-specific functional data from eligible studies (Kato, Kotler, Giacomelli, Funk, Kawaguchi) are available. The VCEP BS3 rules require functional assay outcomes (functional/partially functional/non-functional on Kato data and LOF status across additional assays) that are not available for this variant.	vcep_functional_worksheet
BS4	Not assessed	VCEP BS4 requires lack of segregation in affected family members with LFS-associated cancers. No segregation data are available.
BP1	N/A	VCEP TP53 specifications mark BP1 as Not Applicable; this rule does not apply to TP53 because truncating variants account for only a portion of disease-causing variants.
BP2	N/A	VCEP TP53 specifications mark BP2 as Not Applicable for this gene.
BP3	N/A	VCEP TP53 specifications mark BP3 as Not Applicable for this gene.
BP4	Not met	This is a 2-amino-acid in-frame deletion, which is not covered by the VCEP BP4 rules. VCEP BP4 addresses missense variants (BayesDel ≤ -0.008 and SpliceAI < 0.2), single amino acid in-frame deletions (BayesDel < 0.16 and SpliceAI < 0.2), and silent/intronic variants (SpliceAI ≤ 0.1). SpliceAI max delta is 0.00, but the variant type is outside the scope of the VCEP BP4 framework.	spliceai
BP5	N/A	VCEP TP53 specifications mark BP5 as Not Applicable for this gene.
BP6	N/A	VCEP TP53 specifications mark BP6 as Not Applicable for this gene.
BP7	N/A	VCEP BP7 applies to synonymous (silent) variants or intronic variants outside canonical splice sites. This variant is an in-frame deletion in the coding region.

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