Final classification

VUS

PM2PP3BS3

TP53

c.587G>T

p.Arg196Leu

This variant

The TP53 c.587G>T (p.Arg196Leu; p.R196L) variant has been observed in somatic cancers in COSMIC (COSV52667931, n=3) and has been reported in ClinVar as a variant of uncertain significance.

Transcript

NM_000546.6

HGVS · transcript:coding

NM_000546.6:c.587G>T

GRCh38

chr17:7674944 C>A

GRCh37

chr17:7578262 C>A

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v2.4.0 point-based framework: PM2 supporting (+1) + PP3 moderate (+2) + BS3 supporting (-1) = 2 points, which maps to VUS.

Classification rationale

PM2PP3 BS3 VUS

TP53 c.587G>T

The TP53 c.587G>T (p.Arg196Leu; p.R196L) variant has been observed in somatic cancers in COSMIC (COSV52667931, n=3) and has been reported in ClinVar as a variant of uncertain significance.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 VCEP PM2_Supporting population threshold of 0.00003.² In TP53 VCEP-curated functional datasets, Kato transactivation data were partially functional and other eligible assays showed no loss of function, supporting BS3_Supporting rather than PS3.³ TP53 VCEP in silico criteria assign PP3_Moderate for c.587G>T based on aGVGD Class C65 with BayesDel 0.583489; SpliceAI shows no significant splice effect (max delta 0.14), and REVEL is high at 0.933.⁴

PM2 + PP3 + BS3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

4 vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000546.6 · variants mapped to exon structure

TP53 NM_000546.6

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the TP53 PM2_Supporting threshold of 0.00003 overall allele frequency and below the single-population threshold of 0.00004.

Absent from gnomAD v2.1Absent from gnomAD v4.1TP53 VCEP PM2 threshold <0.00003 overall AF

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 moderate Pathogenic

TP53 VCEP precomputed in silico assessment assigns PP3_Moderate for c.587G>T. The PP3/BP4 worksheet lists aGVGD Class C65 with BayesDel 0.583489, which is above the TP53 PP3_Moderate BayesDel threshold of 0.16; REVEL is also high at 0.933. SpliceAI shows no significant splice effect with a maximum delta score of 0.14.

PP3-BP4 row: c.587G>Tp.Arg196LeuClass C65

spliceai ↗

BS3 supporting Benign

In TP53 VCEP-curated functional datasets, this variant was partially functional in Kato transactivation data and showed no loss of function across other eligible assays. These results support BS3_Supporting and argue against a damaging loss-of-function effect.

Functional worksheet row: R196LKato result: partially functionalother eligible assays: noLOF

PMID:12826609 ↗PMID:29979965 ↗PMID:30224644 ↗

Assessed · not applied · 5 not met · 8 not assessed

Pathogenic

PS1 No established TP53 expert-panel pathogenic or likely pathogenic variant producing the same amino acid change was confirmed from the available records, so PS1 was not assessed.

PS2 No confirmed de novo observation with the phenotype-specific TP53 point framework was identified, so PS2 was not assessed.

PS3 TP53 VCEP-curated functional data do not support loss of function for this variant.

PS4 Although this variant is rare in population databases, no scored series of independent TP53-associated probands was identified to meet the TP53 PS4 point thresholds, so PS4 was not assessed.

PM1 Codon 196 is not one of the TP53 VCEP predefined hotspot codons, and a qualifying Cancer Hotspots exact-variant recurrence count was not verified.

PM5 No verified TP53 expert-panel pathogenic or likely pathogenic missense comparator at codon 196 was confirmed from the available records, so PM5 was not assessed.

PP1 No segregation data with counted informative meioses were identified for this variant, so PP1 was not assessed.

PP4 No observation data with variant allele fraction in the TP53 mosaicism range were identified, so PP4 was not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BA1 stand-alone benign frequency threshold of 0.001.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the TP53 BS1 benign strong frequency threshold of 0.0003.

BS2 No single-source series of unaffected older female carriers was identified, so BS2 was not assessed.

BS4 No non-segregation data in affected relatives were identified for this variant, so BS4 was not assessed.

BP4 Available computational evidence does not support BP4.

N/A · 12 PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 100814)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.933. BayesDel score = 0.583489.

SpliceAI ↗

Functional Inconclusive

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52667931, n = 3 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Understanding the function-structure and function-mutation relationships of p53

PMID 12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supporting

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer

PMID 29979965 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supporting

Mutational processes shape the landscape of TP53 mutations in human cancer.

PMID 30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supporting

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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