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 computer assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.733G>A (p.Gly245Ser)

CA000367

12365 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ed201831-1d8d-4c6d-ad13-1055f8d3407b
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.6:c.733G>A
NM_000546.6(TP53):c.733G>A (p.Gly245Ser)
NC_000017.11:g.7674230C>T
CM000679.2:g.7674230C>T
NC_000017.10:g.7577548C>T
CM000679.1:g.7577548C>T
NC_000017.9:g.7518273C>T
NG_017013.2:g.18321G>A
ENST00000503591.2:c.733G>A
ENST00000508793.6:c.733G>A
ENST00000509690.6:c.337G>A
ENST00000514944.6:c.454G>A
ENST00000604348.6:c.712G>A
ENST00000269305.9:c.733G>A
ENST00000269305.8:c.733G>A
ENST00000359597.8:c.733G>A
ENST00000413465.6:c.733G>A
ENST00000420246.6:c.733G>A
ENST00000445888.6:c.733G>A
ENST00000455263.6:c.733G>A
ENST00000504290.5:c.337G>A
ENST00000504937.5:c.337G>A
ENST00000509690.5:c.337G>A
ENST00000510385.5:c.337G>A
ENST00000514944.5:c.454G>A
ENST00000610292.4:c.616G>A
ENST00000610538.4:c.616G>A
ENST00000610623.4:c.256G>A
ENST00000615910.4:c.700G>A
ENST00000617185.4:c.733G>A
ENST00000618944.4:c.256G>A
ENST00000619186.4:c.256G>A
ENST00000619485.4:c.616G>A
ENST00000620739.4:c.616G>A
ENST00000622645.4:c.616G>A
ENST00000635293.1:c.616G>A
NM_000546.5:c.733G>A
NM_001126112.2:c.733G>A
NM_001126113.2:c.733G>A
NM_001126114.2:c.733G>A
NM_001126115.1:c.337G>A
NM_001126116.1:c.337G>A
NM_001126117.1:c.337G>A
NM_001126118.1:c.616G>A
NM_001276695.1:c.616G>A
NM_001276696.1:c.616G>A
NM_001276697.1:c.256G>A
NM_001276698.1:c.256G>A
NM_001276699.1:c.256G>A
NM_001276760.1:c.616G>A
NM_001276761.1:c.616G>A
NM_001276695.2:c.616G>A
NM_001276696.2:c.616G>A
NM_001276697.2:c.256G>A
NM_001276698.2:c.256G>A
NM_001276699.2:c.256G>A
NM_001276760.2:c.616G>A
NM_001276761.2:c.616G>A
NM_001126112.3:c.733G>A
NM_001126113.3:c.733G>A
NM_001126114.3:c.733G>A
NM_001126115.2:c.337G>A
NM_001126116.2:c.337G>A
NM_001126117.2:c.337G>A
NM_001126118.2:c.616G>A
NM_001276695.3:c.616G>A
NM_001276696.3:c.616G>A
NM_001276697.3:c.256G>A
NM_001276698.3:c.256G>A
NM_001276699.3:c.256G>A
NM_001276760.3:c.616G>A
NM_001276761.3:c.616G>A
More

Pathogenic

Met criteria codes 7
PS2_Moderate PS4 PS3 PP3 PM1 PM2_Supporting PP4_Moderate
Not Met criteria codes 10
PVS1 BA1 BS4 BS1 BS3 BS2 BP4 PS1 PP1 PM5

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.733G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by serine at amino acid 245 (p.Gly245Ser). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor: SCV000184981.8). This variant has been reported in an additional individual meeting Classical criteria and 11 individuals meeting Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 11370630, 32156018, 32888145, 33245408, 34670578, 35974385, 20522432, 24122735, Internal lab contributor: SCV000184981.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000184981.8). This variant has an allele frequency of 0.000002543 (3/1179926 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 non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1). Computational predictor scores (BayesDel = 0.5536; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2_Moderate, PS4_Very Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PP3. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PS2_Moderate
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; Internal lab contributor: SCV000184981.8).
PS4
PS4_VERY STRONG APPLIED This variant has been reported in 1 individual meeting Classical criteria and 11 individuals meeting Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 11370630, 32156018, 32888145, 33245408, 34670578, 35974385, 20522432, 24122735, Internal lab contributor: SCV000184981.8).
PS3
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).
PP3
Computational predictor scores (BayesDel = 0.5536; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).
PM1
This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1).
PM2_Supporting
This variant has an allele frequency of 0.000002543 (3/1179926 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).
PP4_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000184981.8).
Not Met criteria codes
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
BS4
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
BS3
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
BP4
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
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
Two different missense variants (c.733G>C, c.733G>T) in the same codon have been reported (ClinVar IDs 376604, 12349). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP's specifications (PM5 not evaluated).
Curation History
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