clinical submission Queued
Pathogenic for Li-Fraumeni syndrome.
This is a calibration record and does not transfer evidence weight automatically to other TP53 variants.
Case 02 · Expert-panel control
Evidence snapshot 2026-07-17
TP53c.743G>ANP_000537.3:p.Arg248Gln
The R248Q calibration case
What does a clearer evidence record look like when compared with a conflicted variant in the same domain?
Record statusclearNot a clinical verdict
Classification recordLi-Fraumeni syndrome
- 2024-08-05PathogenicClinGen TP53 Variant Curation Expert Panel
Exhibit A · deposited structure
1TSR / ARG B 248 (R248Q site)
Loading local coordinates…
Author chain B, residue 248 · label chain D, seq 155
Court recordEvent 1/7
Now hearing
Case called to order
A TP53 missense variant with an expert-panel ClinVar classification and convergent functional evidence.
Variation ID12356
TranscriptNM_000546.6
Source pack2 records
Deterministic hearing replay
Same evidence. Same order. Every time.
0:001:10
The evidentiary record
Four lanes. No hidden weighting.
Claims are extractive, source-linked, and scoped to their model. Queued cards remain readable before their scheduled entrance.
Supporting evidence
Mechanistic or functional observations that support disruption.
Strong argument
The expert-panel submission and its functional synthesis support a clear calibration record.
functional Queued
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3).
ClinGen VCEP synthesis of yeast and human cell-line assays
The expert-panel statement synthesizes multiple assays with different designs.
Challenging evidence
Observations that resist a simple loss-of-function account.
Limited argument
The expert-panel synthesis combines multiple assay designs and endpoints that remain distinct.
functional Queued
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3).
ClinGen VCEP synthesis of yeast and human cell-line assays
The expert-panel statement synthesizes multiple assays with different designs.
Method review
Assay design, model limits, and comparability checks.
Moderate argument
Functional interpretation combines curated yeast and human-cell assays in an expert-panel synthesis.
functional Queued
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3).
ClinGen VCEP synthesis of yeast and human cell-line assays
The expert-panel statement synthesizes multiple assays with different designs.
Population context
Frequency context that informs but does not decide the record.
Limited argument
The linked ClinVar record reports a low population frequency as contextual evidence.
population Queued
The Genome Aggregation Database (gnomAD) 0.00002.
Population allele-frequency database
Population frequency is one evidence component and changes with database releases.
Cross-examination
A clearer record, with boundaries
Yeast and human-cell assays answer related but different questions within the expert-panel synthesis.
1 cited exhibitsThe expert-panel result belongs to R248Q and cannot be transferred to R282Q.
1 cited exhibitsFinal case file
The record is still being heard.
Complete the replay or unseal the structured summary now.
Evidence admission lab
Add one prepared record. Inspect what changes.
Admission expands the record; it does not rewrite the clinical status. The before/after diff is deterministic and fully inspectable.
Prepared candidate · pubmed
Folding of tetrameric p53: oligomerization and tumorigenic mutations induce misfolding and loss of function
We characterize the stability and conformational state of the tumorigenic DBD mutants R248Q, R249S, and R282Q using equilibrium denaturation and functional assays.