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.537T>A (p.His179Gln)

CA16615708

406578 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2f0057b7-4b8d-4b05-98bd-c7760ee4259c
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.6:c.537T>A
NM_000546.6(TP53):c.537T>A (p.His179Gln)
NC_000017.11:g.7675075A>T
CM000679.2:g.7675075A>T
NC_000017.10:g.7578393A>T
CM000679.1:g.7578393A>T
NC_000017.9:g.7519118A>T
NG_017013.2:g.17476T>A
ENST00000503591.2:c.537T>A
ENST00000508793.6:c.537T>A
ENST00000509690.6:c.141T>A
ENST00000514944.6:c.258T>A
ENST00000604348.6:c.516T>A
ENST00000269305.9:c.537T>A
ENST00000269305.8:c.537T>A
ENST00000359597.8:c.537T>A
ENST00000413465.6:c.537T>A
ENST00000420246.6:c.537T>A
ENST00000445888.6:c.537T>A
ENST00000455263.6:c.537T>A
ENST00000504290.5:c.141T>A
ENST00000504937.5:c.141T>A
ENST00000505014.5:n.793T>A
ENST00000509690.5:c.141T>A
ENST00000510385.5:c.141T>A
ENST00000514944.5:c.258T>A
ENST00000574684.1:n.45T>A
ENST00000610292.4:c.420T>A
ENST00000610538.4:c.420T>A
ENST00000610623.4:c.60T>A
ENST00000615910.4:c.504T>A
ENST00000617185.4:c.537T>A
ENST00000618944.4:c.60T>A
ENST00000619186.4:c.60T>A
ENST00000619485.4:c.420T>A
ENST00000620739.4:c.420T>A
ENST00000622645.4:c.420T>A
ENST00000635293.1:c.420T>A
NM_000546.5:c.537T>A
NM_001126112.2:c.537T>A
NM_001126113.2:c.537T>A
NM_001126114.2:c.537T>A
NM_001126115.1:c.141T>A
NM_001126116.1:c.141T>A
NM_001126117.1:c.141T>A
NM_001126118.1:c.420T>A
NM_001276695.1:c.420T>A
NM_001276696.1:c.420T>A
NM_001276697.1:c.60T>A
NM_001276698.1:c.60T>A
NM_001276699.1:c.60T>A
NM_001276760.1:c.420T>A
NM_001276761.1:c.420T>A
NM_001276695.2:c.420T>A
NM_001276696.2:c.420T>A
NM_001276697.2:c.60T>A
NM_001276698.2:c.60T>A
NM_001276699.2:c.60T>A
NM_001276760.2:c.420T>A
NM_001276761.2:c.420T>A
NM_001126112.3:c.537T>A
NM_001126113.3:c.537T>A
NM_001126114.3:c.537T>A
NM_001126115.2:c.141T>A
NM_001126116.2:c.141T>A
NM_001126117.2:c.141T>A
NM_001126118.2:c.420T>A
NM_001276695.3:c.420T>A
NM_001276696.3:c.420T>A
NM_001276697.3:c.60T>A
NM_001276698.3:c.60T>A
NM_001276699.3:c.60T>A
NM_001276760.3:c.420T>A
NM_001276761.3:c.420T>A
More

Pathogenic

Met criteria codes 6
PS2_Moderate PS3 PM2_Supporting PS1_Moderate PM1 PP4_Moderate
Not Met criteria codes 10
BS4 BS3 BS1 BS2 BP4 PS4 BA1 PP1 PP3 PM6

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.537T>A variant in TP53 is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 179 (p.His179Gln). 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 (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 12 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369). The same amino acid change (p.His179Gln), resulting from a different nucleotide change (c.537T>G) (ClinVar Variation ID: 376607; PMIDs: 18511570, 31119730), is classified as likely pathogenic for Li-Fraumeni syndrome by following the ClinGen TP53 VCEP’s specifications. Splicing prediction using SpliceAI revealed no expected impact on splicing due to either variant (PS1_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 19556618). 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 contributor: SCV000664423.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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: PS3, PM1, PS1_Moderate, PS2_Moderate, PP4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PS2_Moderate
This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 19556618).
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 (PS3; PMIDs: 12826609, 30224644, 29979965).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PS1_Moderate
The same amino acid change (p.His179Gln), resulting from a different nucleotide change (c.537T>G) (ClinVar Variation ID: 376607; PMIDs: 18511570, 31119730), is classified as likely pathogenic for Li-Fraumeni syndrome by following the ClinGen TP53 VCEP’s specifications. Splicing prediction using SpliceAI revealed no expected impact on splicing due to either variant (PS1_Moderate).
PM1
This variant has 12 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369).
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 contributor: SCV000664423.4).
Not Met criteria codes
BS4
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
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
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PS4
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
PP3
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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