Variant classification summary

NM_000546.5:c.214_215delinsTG

TP53 · NP_000537.3:p.(Pro72Cys) · NM_000546.5

GRCh37: chr17:7579472 GG>CA · GRCh38: chr17:7676154 GG>CA

Gene: TP53 Transcript: NM_000546.5

Final call

VUS

PM2 supporting

Variant details

Gene

TP53

Transcript

NM_000546.5

Protein

NP_000537.3:p.(Pro72Cys)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000546.5:c.214_215delinsTG (p.Pro72Cys) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting per TP53 VCEP criteria (allele frequency <0.003%).

2

PVS1 is not applicable as the variant is an in-frame delins resulting in a single amino acid substitution (p.Pro72Cys), not a null variant covered by the VCEP PVS1 flowchart.

3

No functional data (PS3/BS3) is available for this variant; p.Pro72Cys is not listed in the VCEP Functional-worksheet and no variant-specific functional studies were identified in the reviewed literature.

4

No pathogenic or likely pathogenic variant has been established at codon 72 (Pro72), which precludes application of PS1 and PM5. All single-nucleotide missense variants at this residue receive BP4_moderate per the VCEP.

5

In silico scores (REVEL, BayesDel) are not computable for delins variants, precluding PP3/BP4 assessment.

6

Codon 72 is not a recognized TP53 hotspot; the variant lies outside VCEP-designated hotspot codons 175, 245, 248, 249, 273, and 282, and is not listed in cancerhotspots.org.

7

No proband clinical data, de novo observations, segregation data, or elderly cancer-free carrier data are available for this variant, precluding PS2, PS4, PP1, PP4, BS2, and BS4.

8

This variant has been reported in ClinVar as Uncertain Significance, with 7 clinical laboratories reporting Uncertain Significance, 1 reporting Likely Benign, and the ClinGen TP53 VCEP Expert Panel classifying as Uncertain Significance (ClinVar ID: 182953).

9

Applying the TP53 VCEP Tavtigian point-based classification system: only PM2_Supporting (1 point) is met, yielding a total of 1 point, which falls within the Uncertain Significance range (-1 to 5 points).

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_000546.5:c.214_215delinsTG results in a single amino acid substitution (p.Pro72Cys), not a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion). PVS1 applies only to null variants per the TP53 VCEP PVS1 flowchart.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No pathogenic or likely pathogenic variant has been established at codon 72 (Pro72) per the TP53 VCEP. The VCEP PP3-BP4 spreadsheet assigns BP4_moderate to all single-nucleotide missense variants at this residue. The functional worksheet lists R72 variants with 'No evidence' or BS3 codes.	cspec vcep_pp3_bp4_codes vcep_functional_worksheet
PS2	Not met	No de novo observation has been reported for NM_000546.5:c.214_215delinsTG. No proband data with confirmed parentage is available.
PS3	Not assessed	The variant p.Pro72Cys is not listed in the TP53 VCEP Functional-worksheet (Supplementary Table S3). No functional data from Kato, Funk, Giacomelli, Kotler, or Kawaguchi assays is available. None of the reviewed publications contain variant-specific functional evidence for this variant.	vcep_functional_worksheet
PS4	Not met	No probands meeting Li-Fraumeni syndrome clinical criteria with this variant have been identified in the available evidence. No PS4 points can be scored without proband-level clinical data.	cspec
PS5	N/A	PS5 is not part of the TP53 VCEP framework. The VCEP uses PP5, which is designated as Not Applicable per ClinGen SVI VCEP Review Committee recommendation.	cspec
PM1	Not met	Codon 72 (Pro72) is not among the VCEP-designated TP53 hotspot codons (175, 245, 248, 249, 273, 282). The variant is not listed in cancerhotspots.org with sufficient somatic occurrences for the same amino acid change.	cspec
PM2	Met	NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency = 0), which is below the VCEP PM2_Supporting threshold of <0.00003 (0.003%).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. The VCEP does not use PM4 for TP53 variant classification.	cspec
PM5	Not met	The variant is a delins resulting in a single amino acid substitution (Pro72Cys) rather than a classic single-nucleotide missense variant. Regardless, no pathogenic or likely pathogenic missense variant has been established at Pro72 per the TP53 VCEP. PM5 requires a different established pathogenic variant at the same residue.	cspec pm5_candidates
PM6	N/A	PM6 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel.	cspec
PP1	Not met	No cosegregation data is available for this variant. No families with multiple affected members carrying NM_000546.5:c.214_215delinsTG have been reported.
PP2	N/A	PP2 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Missense variants account for the majority of pathogenic TP53 variants.	cspec
PP3	Not assessed	REVEL and BayesDel scores are not computable for delins variants — they are designed for single nucleotide variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. No in silico pathogenicity prediction can be applied under the VCEP framework.	vcep_pp3_bp4_codes
PP4	Not met	No patient-specific phenotype or variant allele fraction (VAF) data is available. PP4 requires observation of the variant at low VAF (5-35%) suggestive of somatic mosaicism or constitutional mosaicism.	cspec
PP5	N/A	PP5 is designated as Not Applicable by the ClinGen SVI VCEP Review Committee. The TP53 VCEP does not use this criterion.	cspec
BA1	Not met	NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The BA1 threshold of FAF ≥ 0.001 (0.1%) in any continental subpopulation is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_000546.5:c.214_215delinsTG is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The BS1 threshold of FAF ≥ 0.0003 (0.03%) in any continental subpopulation is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data is available on healthy elderly females (≥60 years without cancer) carrying this variant. BS2 requires ≥2 unrelated females meeting these criteria from a single source.
BS3	Not assessed	The variant p.Pro72Cys is not listed in the TP53 VCEP Functional-worksheet (Supplementary Table S3). No functional data from eligible assays (Kato, Funk, Giacomelli, Kotler, Kawaguchi) is available. The variant lacks pre-assigned functional codes from the VCEP.	vcep_functional_worksheet
BS4	Not met	No segregation data is available. BS4 requires lack of segregation in affected family members diagnosed with LFS-associated cancers.
BP1	N/A	BP1 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. Truncating variants account for only a portion of disease-causing TP53 variants.	cspec
BP2	N/A	BP2 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel.	cspec
BP3	N/A	BP3 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel. This criterion concerns in-frame deletions/insertions in repetitive regions without known function, which is not assessed under the VCEP.	cspec
BP4	Not assessed	BayesDel and REVEL scores are not computable for delins variants. The VCEP PP3-BP4-codes.xlsx does not include this variant. While single-nucleotide substitutions at Pro72 consistently receive BP4_moderate (BayesDel scores from -0.10 to -0.21), these scores cannot be directly applied to a delins variant.	vcep_pp3_bp4_codes
BP5	N/A	BP5 is designated as Not Applicable by the ClinGen TP53 Variant Curation Expert Panel.	cspec
BP6	N/A	BP6 is designated as Not Applicable by the ClinGen SVI VCEP Review Committee. The TP53 VCEP does not use this criterion.	cspec
BP7	N/A	BP7 applies to synonymous (silent) or intronic variants. NM_000546.5:c.214_215delinsTG is neither synonymous nor intronic — it results in a missense substitution (p.Pro72Cys).	cspec

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