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.524G>T (p.Arg175Leu)

CA000252

182963 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6aa7e5db-edd6-4608-a046-e82aa9ea21df
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

NM_000546.6:c.524G>T
NM_000546.6(TP53):c.524G>T (p.Arg175Leu)
NC_000017.11:g.7675088C>A
CM000679.2:g.7675088C>A
NC_000017.10:g.7578406C>A
CM000679.1:g.7578406C>A
NC_000017.9:g.7519131C>A
NG_017013.2:g.17463G>T
ENST00000503591.2:c.524G>T
ENST00000508793.6:c.524G>T
ENST00000509690.6:c.128G>T
ENST00000514944.6:c.245G>T
ENST00000604348.6:c.503G>T
ENST00000269305.9:c.524G>T
ENST00000269305.8:c.524G>T
ENST00000359597.8:c.524G>T
ENST00000413465.6:c.524G>T
ENST00000420246.6:c.524G>T
ENST00000445888.6:c.524G>T
ENST00000455263.6:c.524G>T
ENST00000504290.5:c.128G>T
ENST00000504937.5:c.128G>T
ENST00000505014.5:n.780G>T
ENST00000509690.5:c.128G>T
ENST00000510385.5:c.128G>T
ENST00000514944.5:c.245G>T
ENST00000574684.1:n.32G>T
ENST00000610292.4:c.407G>T
ENST00000610538.4:c.407G>T
ENST00000610623.4:c.47G>T
ENST00000615910.4:c.491G>T
ENST00000617185.4:c.524G>T
ENST00000618944.4:c.47G>T
ENST00000619186.4:c.47G>T
ENST00000619485.4:c.407G>T
ENST00000620739.4:c.407G>T
ENST00000622645.4:c.407G>T
ENST00000635293.1:c.407G>T
NM_000546.5:c.524G>T
NM_001126112.2:c.524G>T
NM_001126113.2:c.524G>T
NM_001126114.2:c.524G>T
NM_001126115.1:c.128G>T
NM_001126116.1:c.128G>T
NM_001126117.1:c.128G>T
NM_001126118.1:c.407G>T
NM_001276695.1:c.407G>T
NM_001276696.1:c.407G>T
NM_001276697.1:c.47G>T
NM_001276698.1:c.47G>T
NM_001276699.1:c.47G>T
NM_001276760.1:c.407G>T
NM_001276761.1:c.407G>T
NM_001276695.2:c.407G>T
NM_001276696.2:c.407G>T
NM_001276697.2:c.47G>T
NM_001276698.2:c.47G>T
NM_001276699.2:c.47G>T
NM_001276760.2:c.407G>T
NM_001276761.2:c.407G>T
NM_001126112.3:c.524G>T
NM_001126113.3:c.524G>T
NM_001126114.3:c.524G>T
NM_001126115.2:c.128G>T
NM_001126116.2:c.128G>T
NM_001126117.2:c.128G>T
NM_001126118.2:c.407G>T
NM_001276695.3:c.407G>T
NM_001276696.3:c.407G>T
NM_001276697.3:c.47G>T
NM_001276698.3:c.47G>T
NM_001276699.3:c.47G>T
NM_001276760.3:c.407G>T
NM_001276761.3:c.407G>T
More

Likely Pathogenic

Met criteria codes 7
BS3_Supporting PS4_Moderate PP3_Moderate PM2_Supporting PP4 PM5 PM1
Not Met criteria codes 8
BS1 BS2 BP4 PS1 PS2 PS3 BA1 PP1

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.524G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 175 (p.Arg175Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae). 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 (PM1; PMID: 8023157). Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PM2_Supporting, BS3_Supporting, PP3_Moderate, PP4, PM1, PM5 (Bayesian Points: 9; VCEP specifications version 2.0; 9/6/2024)
Met criteria codes
BS3_Supporting
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644,).
PS4_Moderate
This variant has been reported in 4 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMID: 16707427; Internal lab contributors: Invitae, Ambry).
PP3_Moderate
Computational predictor scores (BayesDel = 0.57303; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PP4
At least one individual with this variant was found to have a variant allele fraction of ≤35%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: Invitae).
PM5
Another missense variant(c.524G>A, p.Arg175His) (ClinVar Variation ID: 12374), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5).
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 (PM1; PMID: 8023157).
Not Met criteria codes
BS1
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
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
BA1
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
Curation History
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