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]
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  • 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_000546.5(TP53):c.538G>A (p.Glu180Lys)

CA10584590

245711 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 63dea6d6-388c-4d5b-a692-7a92656a24d8
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.538G>A
NM_000546.5(TP53):c.538G>A (p.Glu180Lys)
NC_000017.11:g.7675074C>T
CM000679.2:g.7675074C>T
NC_000017.10:g.7578392C>T
CM000679.1:g.7578392C>T
NC_000017.9:g.7519117C>T
NG_017013.2:g.17477G>A
ENST00000503591.2:c.538G>A
ENST00000508793.6:c.538G>A
ENST00000509690.6:c.142G>A
ENST00000514944.6:c.259G>A
ENST00000604348.6:c.517G>A
ENST00000269305.9:c.538G>A
ENST00000269305.8:c.538G>A
ENST00000359597.8:c.538G>A
ENST00000413465.6:c.538G>A
ENST00000420246.6:c.538G>A
ENST00000445888.6:c.538G>A
ENST00000455263.6:c.538G>A
ENST00000504290.5:c.142G>A
ENST00000504937.5:c.142G>A
ENST00000505014.5:n.794G>A
ENST00000509690.5:c.142G>A
ENST00000510385.5:c.142G>A
ENST00000514944.5:c.259G>A
ENST00000574684.1:n.46G>A
ENST00000610292.4:c.421G>A
ENST00000610538.4:c.421G>A
ENST00000610623.4:c.61G>A
ENST00000615910.4:c.505G>A
ENST00000617185.4:c.538G>A
ENST00000618944.4:c.61G>A
ENST00000619186.4:c.61G>A
ENST00000619485.4:c.421G>A
ENST00000620739.4:c.421G>A
ENST00000622645.4:c.421G>A
ENST00000635293.1:c.421G>A
NM_001126112.2:c.538G>A
NM_001126113.2:c.538G>A
NM_001126114.2:c.538G>A
NM_001126115.1:c.142G>A
NM_001126116.1:c.142G>A
NM_001126117.1:c.142G>A
NM_001126118.1:c.421G>A
NM_001276695.1:c.421G>A
NM_001276696.1:c.421G>A
NM_001276697.1:c.61G>A
NM_001276698.1:c.61G>A
NM_001276699.1:c.61G>A
NM_001276760.1:c.421G>A
NM_001276761.1:c.421G>A
NM_001276695.2:c.421G>A
NM_001276696.2:c.421G>A
NM_001276697.2:c.61G>A
NM_001276698.2:c.61G>A
NM_001276699.2:c.61G>A
NM_001276760.2:c.421G>A
NM_001276761.2:c.421G>A
NM_000546.6:c.538G>A
NM_001126112.3:c.538G>A
NM_001126113.3:c.538G>A
NM_001126114.3:c.538G>A
NM_001126115.2:c.142G>A
NM_001126116.2:c.142G>A
NM_001126117.2:c.142G>A
NM_001126118.2:c.421G>A
NM_001276695.3:c.421G>A
NM_001276696.3:c.421G>A
NM_001276697.3:c.61G>A
NM_001276698.3:c.61G>A
NM_001276699.3:c.61G>A
NM_001276760.3:c.421G>A
NM_001276761.3:c.421G>A

Likely Pathogenic

Met criteria codes 4
PP3 PM2_Supporting PS3_Moderate PS4
Not Met criteria codes 12
PP4 PP1 BA1 PM5 PM1 PM6 BS4 BS3 BS1 PS1 PS2 BP4

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.538G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 180 (p.Glu180Lys). This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.262; 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 Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4; PM2_Supporting, PS3_Moderate; PP3. (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PP3
Computational predictor scores (BayesDel = 0.262; 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).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PS3_Moderate
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965).
PS4
This variant has been reported in 12 unrelated families meeting Revised Chompret criteria and reported in 1 individual with a HER2+ breast cancer. Based on this evidence, this variant scores 7 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 35974385, 33178583, 25584008, 8118819; Internal lab contributors: SCV000629836.7, SCV000581143.5, SCV000292772.10).
Not Met criteria codes
PP4
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
2 different missense variants (c.540G>T, p.Glu180Asp and c.540G>C, p.Glu180Asp) in the same codon have been reported (ClinVar Variation IDs: 1521256, 1509915). 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).
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
PM6
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
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
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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