Final classification

Likely Pathogenic

PS3PM1PM2PP3PP5

TP53

c.1031T>G

p.Leu344Arg

missense · exon 10

Gene context NCBI Gene ↗ OncoKB ↗

TP53 encodes the p53 tumor suppressor protein, a transcription factor that responds to cellular stress such as DNA damage by switching on genes that trigger cell cycle arrest, DNA repair, senescence, or programmed cell death. In healthy cells, p53 is kept at low levels by constant degradation, but stress signals stabilize and activate it to protect against damaged cells surviving and dividing. Inherited mutations in TP53 cause Li-Fraumeni syndrome, a condition marked by a high risk of developing multiple cancers at a young age. TP53 is the most commonly mutated gene across human cancers, and loss of its normal function promotes tumor growth, spread, drug resistance, and genomic instability.

This variant

TP53 encodes a stress-responsive tumor suppressor, and inherited TP53 loss-of-function variants cause Li-Fraumeni syndrome with autosomal-dominant predisposition to multiple early-onset cancers.

Transcript

NM_000546.5

HGVS · transcript:coding

NM_000546.5:c.1031T>G

GRCh38

chr17:7670678 A>C

GRCh37

chr17:7573996 A>C

Likely Pathogenic: PS3 strong, PP3 moderate, and PM1, PM2, and PP5 supporting total 9 points under the TP53 VCEP framework.

Classification rationale

PS3PM1PM2PP3PP5 Likely Pathogenic

TP53 c.1031T>G missense · exon 10

PS3 strong: TP53 VCEP functional data show absent reporter activity and abnormal oligomerization for L344R. PM1 supporting: p.Leu344Arg has 7 same-amino-acid-change hotspot occurrences. PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1. PP3 moderate: the TP53 VCEP lookup table assigns PP3 moderate based on BayesDel class C65 and score 0.288212. PP5 supporting: the ClinVar TP53 Expert Panel classifies the exact variant as Likely Pathogenic.

PS3 + PM1 + PM2 + PP3 + PP5 → Likely Pathogenic

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_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 5 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 · 5

Strength Supporting Moderate Strong Very strong

PS3 strong Pathogenic

Met, strong: the TP53 VCEP worksheet assigns PS3 to L344R, supported by absent reporter activity and a 98.2% ± 1.7% monomer fraction.

The exact L344R row in Functional-worksheet.xlsx records Non-functional and LOF assay results and assigns preliminary functional code PS3.The TP53 VCEP functional flowchart identifies Kato, Funk, Giacomelli, Kotler, and Kawaguchi as eligible functional studies and directs use of the functional worksheet for pre-assigned codes.In p53-null H1299 cells, L344R produced no DsRed reporter signal; the extracted study reports a 98.2% ± 1.7% monomer fraction for L344R versus 45.8% ± 3.3% for wild type.

cspec ↗PMID:19454241 ↗PMID:16007150 ↗

PM1 supporting Pathogenic

Met at Supporting: p.Leu344Arg has 7 same-amino-acid-change hotspot occurrences, within the VCEP's 2-9 occurrence threshold.

The TP53 VCEP PM1 Moderate rule limits codon-based application to codons 175, 245, 248, 249, 273, and 282; it also requires at least 10 same-amino-acid-change Cancer Hotspots occurrences for the alternative Moderate route.The TP53 VCEP PM1 Supporting rule requires 2-9 same-amino-acid-change Cancer Hotspots occurrences, and the available record reports 7 occurrences for p.Leu344Arg; the Moderate threshold is not met.PMID:20978130 places L344R in the TP53 tetramerization domain, but the TP53 VCEP PM1 rule does not authorize this domain alone as an additional PM1 route.

cspec ↗PMID:20978130 ↗

PM2 supporting Pathogenic

Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with frequency 0 versus the TP53 PM2 threshold of <0.00003.

TP53 VCEP v2.4 PM2 rule: apply at supporting strength for allele frequency <0.00003 (0.003%) in gnomAD or another large sequenced population; if multiple alleles occur in an ancestry group, that group's frequency must be <0.00004 (0.004%), excluding founder-effect groups.gnomAD v2.1 all-comers: variant absent.gnomAD v4.1 all-comers: variant absent.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 moderate Pathogenic

Met at moderate: the TP53 VCEP lookup table directly assigns PP3_moderate to c.1031T>G with BayesDel 0.288212 and SpliceAI 0.01.

The TP53 VCEP PP3-BP4-codes.xlsx supplementary table entry for c.1031T>G / p.Leu344Arg assigns PP3_moderate, reports BayesDel class C65, BayesDel score 0.288212, and maximum SpliceAI delta 0.01.The TP53 VCEP specification states that missense variants with aGVGD class C65 and BayesDel score >=0.16 meet PP3 at moderate strength; its direct lookup-table pre-assignment is controlling here.The case SpliceAI result reports max delta 0.001, and the VCEP lookup table reports 0.01; both are below the VCEP predicted-splicing threshold of 0.2.

cspec ↗spliceai ↗

PP5 supporting Pathogenic

Met, supporting: the exact ClinVar expert-panel classification is Likely Pathogenic for NM_000546.5:c.1031T>G.

ClinVar variation 2758378 exactly matches NM_000546.5:c.1031T>G (p.Leu344Arg) and reports a Likely Pathogenic classification by the ClinGen TP53 Variant Curation Expert Panel.The expert-panel classification is the qualifying evidence for PP5; clinical-laboratory submissions, the aggregate label, and non-expert assertions were not used to trigger this criterion.ClinVar expert panel classification

clinvar ↗

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

Pathogenic

PS1 Not assessed: no independent pathogenic same-amino-acid-change comparator is available for L344R, and the variant's own ClinVar classification cannot supply PS1 evidence.

PS2 Not assessed: no documented parental testing, confirmed de novo status, proband cancer type, or PS2 point total is available.

PS4 Not assessed: no proband phenotype or per-proband PS4 point total is available to compare with the Supporting threshold of 1-1.5 points.

PM5 Not assessed: L344Q, L344P, and L344M have functional data, but no alternate L344 missense variant has the VCEP-required pathogenic adjudication and qualifying clinical evidence.

PP1 Not assessed: no documented affected relatives, cosegregation observations, or countable meioses are available for comparison with the 3-4 meioses supporting threshold.

PP4 Not assessed: no independent PP4-eligible observation or variant allele fraction is reported for this variant.

Benign

BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so no ancestry-specific FAF reaches the TP53 BA1 threshold of 0.001.

BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, so no ancestry-specific FAF reaches the TP53 BS1 threshold of 0.0003.

BS2 Not assessed: no qualifying unaffected female carriers aged at least 60 years from a single source are reported for comparison with the TP53 BS2 thresholds.

BS3 Not met: the TP53 VCEP worksheet assigns PS3 to L344R, with Non-functional and LOF results rather than benign functional activity.

BS4 Not assessed: no affected relatives with documented variant-negative testing are available to establish lack of segregation.

BP4 Not met: BayesDel 0.288212 exceeds the TP53 VCEP BP4 supporting cutoff of <0.16 despite SpliceAI max delta 0.001.

BP6 Not met: the exact ClinVar expert-panel classification is Likely Pathogenic, not Benign or Likely Benign.

N/A · 10 PVS1 · PM3 · PM4 · PM6 · PP2 · BP1 · BP2 · BP3 · BP5 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 2758378)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.858. BayesDel score = 0.288212.

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53068361, n = 7 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. 5 further PMIDs triaged but not cited — see Sources & references.

The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.

PMID 16007150 ↗ · Kawaguchi T et al. · 2005 Oct 20 CLINVAR · case observation

Searched

c.1031T>GNP_000537.3:p.(L344R)

Found

The paper explicitly evaluated TP53 p.L344R and reported that L344Q, L344P, and L344R were monomer mutants, whereas L344M was a dimer mutant, in an assay of the tetramerization-domain oligomerization interface.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

The exact L344R variant is classified as a monomer mutant, indicating abnormal oligomerization and supporting functional loss.

Interestingly, most of the mutant p53s in F341 (four of six, F341V, F341Y, F341S and F341C) and L344 (three of four, L344Q, L344P and L344R) were monomer mutants, and the remaining mutants contained dimer mutants (F341L and L344M).

Location Results, paragraph describing the dimer–dimer interaction in the oligomerization domain, p. 6979 · Context Comprehensive TP53 missense mutation library; mutant proteins were expressed in yeast and oligomer formation was assessed by glutaraldehyde cross-linking, SDS/PAGE, and immunoblotting. · full text

Evaluation of transcriptional activity of p53 in individual living mammalian cel

PMID 19454241 ↗ ONCOKB · functional

Searched

c.1031T>GNP_000537.3:p.(L344R)

Found

The study explicitly evaluated TP53 L344R in p53-null H1299 cells using an EGFP-p53 construct and a p53-responsive DsRed reporter. L344R produced no DsRed signal in the representative experiments, had a mean DsRed-positive fraction of 3.5% ± 2.4% at the stated expression range versus 24.1% ± 4.1% for wild type, and showed a monomer fraction of 98.2% ± 1.7% versus 45.8% ± 3.3% for wild type.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

Variant-specific absent transcriptional reporter activity and abnormal monomer fraction support loss of function.

Similar to the R273H mutant, no DsRed signals were obtained in the eight mutant p53s in the tetramerization domain of p53: L330H, R337C, R337P, F341C, R342P, L344P, L344R, and M340QL344R (Fig. 2G; see also Supplementary Fig. S1 in supplementary material). The results indicated that mutations of these amino acid residues greatly affected the transcriptional activity of p53.

Location Results, ‘Relationship between expression of p53 and DsRed in reporter assay’; Results, ‘Effect of mutation in tetramerization domain on transcriptional activity of p53’; Table 1 · Context Functional analysis in p53-null H1299 cells transfected with EGFP-p53 constructs and a p53-responsive DsRed reporter; transcriptional activity was assessed by DsRed-positive cells and oligomeric status by fluorescence intensity distribution analysis. · full text

Cancer-associated p53 tetramerization domain mutants: quantitative analysis reve

PMID 20978130 ↗ ONCOKB · functional

Searched

c.1031T>GNP_000537.3:p.(L344R)

Found

The paper explicitly studied TP53 L344R using tetramerization-domain peptides comprising residues 319–358. L344R eluted between tetramer and monomer fractions and was classified as a dimer under the study conditions; the paper also characterized its structure and thermal instability.

Variant

✓ Names this variant — characterised directly

Applied to

→PS3 strong

The exact L344R variant shows abnormal oligomerization and thermal instability rather than normal tetrameric function.

→PM1 supporting

Confirms that L344R lies in the tetramerization domain, while the TP53 VCEP PM1 rule does not authorize this domain alone for PM1.

Interestingly, three mutants (F341C, L344R, and A347T) eluted between the tetramer and monomer fractions. Accordingly, five mutants, L330R/P, R337P, L342P, and L344P, exist as monomers, three mutants, F341C, L344R, and A347T as dimers, and the others as tetramers under our conditions.

Location Results, "Oligomerization State of Mutant p53 Tetramerization Domains"; Discussion · Context Synthetic p53 tetramerization-domain peptides spanning residues 319–358 analyzed by gel-filtration chromatography and circular-dichroism thermal-denaturation measurements. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

20301488 ↗ Li-Fraumeni Syndrome. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics CLINVAR

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