Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.883C>T (p.Pro295Ser)

CA397836496

428862 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 76e4a955-af29-4437-9e32-387b300c80d4
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.6:c.883C>T
NM_000546.6(TP53):c.883C>T (p.Pro295Ser)
NC_000017.11:g.7673737G>A
CM000679.2:g.7673737G>A
NC_000017.10:g.7577055G>A
CM000679.1:g.7577055G>A
NC_000017.9:g.7517780G>A
NG_017013.2:g.18814C>T
ENST00000503591.2:c.883C>T
ENST00000508793.6:c.883C>T
ENST00000509690.6:c.487C>T
ENST00000514944.6:c.604C>T
ENST00000604348.6:c.862C>T
ENST00000269305.9:c.883C>T
ENST00000269305.8:c.883C>T
ENST00000359597.8:c.883C>T
ENST00000413465.6:c.782+444C>T
ENST00000420246.6:c.883C>T
ENST00000445888.6:c.883C>T
ENST00000455263.6:c.883C>T
ENST00000504290.5:c.487C>T
ENST00000504937.5:c.487C>T
ENST00000509690.5:c.487C>T
ENST00000510385.5:c.487C>T
ENST00000610292.4:c.766C>T
ENST00000610538.4:c.766C>T
ENST00000610623.4:c.406C>T
ENST00000615910.4:c.850C>T
ENST00000617185.4:c.883C>T
ENST00000618944.4:c.406C>T
ENST00000619186.4:c.406C>T
ENST00000619485.4:c.766C>T
ENST00000620739.4:c.766C>T
ENST00000622645.4:c.766C>T
ENST00000635293.1:c.766C>T
NM_000546.5:c.883C>T
NM_001126112.2:c.883C>T
NM_001126113.2:c.883C>T
NM_001126114.2:c.883C>T
NM_001126115.1:c.487C>T
NM_001126116.1:c.487C>T
NM_001126117.1:c.487C>T
NM_001126118.1:c.766C>T
NM_001276695.1:c.766C>T
NM_001276696.1:c.766C>T
NM_001276697.1:c.406C>T
NM_001276698.1:c.406C>T
NM_001276699.1:c.406C>T
NM_001276760.1:c.766C>T
NM_001276761.1:c.766C>T
NM_001276695.2:c.766C>T
NM_001276696.2:c.766C>T
NM_001276697.2:c.406C>T
NM_001276698.2:c.406C>T
NM_001276699.2:c.406C>T
NM_001276760.2:c.766C>T
NM_001276761.2:c.766C>T
NM_001126112.3:c.883C>T
NM_001126113.3:c.883C>T
NM_001126114.3:c.883C>T
NM_001126115.2:c.487C>T
NM_001126116.2:c.487C>T
NM_001126117.2:c.487C>T
NM_001126118.2:c.766C>T
NM_001276695.3:c.766C>T
NM_001276696.3:c.766C>T
NM_001276697.3:c.406C>T
NM_001276698.3:c.406C>T
NM_001276699.3:c.406C>T
NM_001276760.3:c.766C>T
NM_001276761.3:c.766C>T
More

Likely Benign

Met criteria codes 3
PM2_Supporting BS3 BP4
Not Met criteria codes 17
PM1 PM5 PVS1 BA1 BS1 BS4 BS2 BP5 BP1 PS1 PS2 PS3 PS4 PP1 PP2 PP3 PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.883C>T variant in TP53 is a missense variant predicted to cause substitution of proline by serine at amino acid 295 (p.Pro295Ser). This variant has an allele frequency of 0.000004237 (5/1180042 alleles) in the European non-Finnish population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.2; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.000004237 (5/1180042 alleles) in the European non-Finnish population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 30224644).
BP4
BP4_MODERATE MET Computational predictor scores (BayesDel = -0.2; Align GVGD Class 0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Another missense variant (c.884C>T, p.Pro295Leu) in the same codon has been reported(ClinVar Variation ID: 420974). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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