PVS1_Moderate applied: frameshift variant c.1154del (p.Phe385SerfsTer37) produces a premature termination codon downstream of the natural stop codon, qualifying for PVS1 at moderate strength per the TP53 VCEP PVS1 flowchart.1 PM2_Supporting applied: variant is extremely rare in population databases (gnomAD v4.1 AF 6.2e-07, 1/1,614,126 alleles), well below the VCEP PM2_Supporting threshold of 0.003%.2 Total pathogenic points: 3 (PVS1_Moderate = 2, PM2_Supporting = 1). Per Tavtigian point-based system adopted by TP53 VCEP v2.4, a score of 3 falls in the range -1 to 5, consistent with Uncertain Significance.3 Functional evidence could not be applied: the TP53 VCEP functional worksheet covers missense variants and small in-frame deletions only; frameshift variants are not represented.4 This variant has been observed in somatic cancers (COSMIC, n=2) and is absent from ClinVar. OncoKB classifies it as Likely Oncogenic with a Likely Loss-of-function biological effect.5
TP53
Final classification
VUS
TP53 c.1154del · p.Phe385SerfsTer37
TP53
PVS1_Moderate applied: frameshift variant c.1154del (p.Phe385SerfsTer37) produces a premature termination codon downstream of the natural stop codon, qualifying for PVS1 at moderate strength per the TP53 VCEP PVS1 flowchart.
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4 v2.4 point-based framework: PVS1 moderate (+2) + PM2 supporting (+1) = 3 points, which maps to VUS.
Classification rationale
PVS1PM2
VUS
TP53 c.1154del
PVS1 + PM2
→
VUS
Gene diagram
· NM_000546.6 · variants mapped to exon structure
TP53
NM_000546.6
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 12 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
moderate
Pathogenic
Frameshift variant NM_000546.6:c.1154del (p.Phe385SerfsTer37) produces a premature termination codon at position 421, downstream of the natural stop codon at p.Asp393. Per the TP53 VCEP PVS1 flowchart, frameshift-induced PTC downstream of the natural stop codon is assigned PVS1_Moderate.
Frameshift deletion in exon 11 (c.1101-*1188)PTC at codon 421downstream of natural stop at codon 394
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. gnomAD v4.1 total allele frequency is 6.2e-07 (1/1,614,126 alleles; 0.000062%), well below the TP53 VCEP PM2_Supporting threshold of 0.003%. The highest subpopulation frequency is South Asian at 0.0011% (1/91,080), below the 0.004% threshold for multiple alleles within a genetic ancestry group. Absent from gnomAD v2.1 and gnomAD-Canada.
gnomAD v4.1: 1/1614126 alleles (AF 6.2e-07)
Assessed · not applied
Pathogenic
PS1
No same-position nucleotide variant has been classified as pathogenic or likely pathogenic under the TP53 VCEP specifications.
PS2
No de novo observation data are available for this variant.
PS3
The TP53 VCEP functional assay worksheet (Supplementary Table S3) covers missense variants and small in-frame deletions only; frameshift variants including c.1154del are not represented.
PS4
No case-control data or proband counts with Li-Fraumeni syndrome-associated cancers are available.
PM1
The TP53 VCEP restricts PM1 to missense variants at codons 175, 245, 248, 249, 273, 282 (moderate), or cancerhotspots.org with sufficient somatic occurrences.
PP1
No cosegregation data are available.
PP4
No patient phenotype data or variant allele fraction (VAF) information is available.
Benign
BA1
The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), well below the VCEP BA1 threshold of 0.1% (FAF ≥0.001).
BS1
The highest subpopulation allele frequency is South Asian at 0.0011% (AF 1.1e-05), below the VCEP BS1 threshold of 0.03% (FAF ≥0.0003).
BS2
No data on unrelated females who have reached at least 60 years of age without cancer.
BS3
The TP53 VCEP functional assay worksheet covers missense variants and small in-frame deletions only.
BS4
No segregation data available.
N/A · 13
PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.1953e-07; MAF= 0.00006%, 1/1614126 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09794e-05; MAF= 0.00110%, 1/91080 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,126
0 hom
0 hom
South Asian 1 / 91,080 |
0.0011% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53389349, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 5 PMIDs not cited in assessment
11753428 ↗
A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer.
ONCOKB
16007150 ↗
The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.
ONCOKB
19336573 ↗
High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer.
ONCOKB
21467160 ↗
Prognostic significance of truncating TP53 mutations in head and neck squamous cell carcinoma.
ONCOKB