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_000546.5(TP53):c.461G>A (p.Gly154Asp)

CA002547

237950 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8aa4ca01-1c6e-4192-b46b-2f5debbca3dc
Approved on: 2025-02-06
Published on: 2025-02-07

HGVS expressions

NM_000546.5:c.461G>A
NM_000546.5(TP53):c.461G>A (p.Gly154Asp)
NC_000017.11:g.7675151C>T
CM000679.2:g.7675151C>T
NC_000017.10:g.7578469C>T
CM000679.1:g.7578469C>T
NC_000017.9:g.7519194C>T
NG_017013.2:g.17400G>A
ENST00000503591.2:c.461G>A
ENST00000508793.6:c.461G>A
ENST00000509690.6:c.65G>A
ENST00000514944.6:c.182G>A
ENST00000604348.6:c.440G>A
ENST00000269305.9:c.461G>A
ENST00000269305.8:c.461G>A
ENST00000359597.8:c.461G>A
ENST00000413465.6:c.461G>A
ENST00000420246.6:c.461G>A
ENST00000445888.6:c.461G>A
ENST00000455263.6:c.461G>A
ENST00000504290.5:c.65G>A
ENST00000504937.5:c.65G>A
ENST00000505014.5:n.717G>A
ENST00000508793.5:c.461G>A
ENST00000509690.5:c.65G>A
ENST00000510385.5:c.65G>A
ENST00000514944.5:c.182G>A
ENST00000610292.4:c.344G>A
ENST00000610538.4:c.344G>A
ENST00000610623.4:c.-17G>A
ENST00000615910.4:c.428G>A
ENST00000617185.4:c.461G>A
ENST00000618944.4:c.-17G>A
ENST00000619186.4:c.-17G>A
ENST00000619485.4:c.344G>A
ENST00000620739.4:c.344G>A
ENST00000622645.4:c.344G>A
ENST00000635293.1:c.344G>A
NM_001126112.2:c.461G>A
NM_001126113.2:c.461G>A
NM_001126114.2:c.461G>A
NM_001126115.1:c.65G>A
NM_001126116.1:c.65G>A
NM_001126117.1:c.65G>A
NM_001126118.1:c.344G>A
NM_001276695.1:c.344G>A
NM_001276696.1:c.344G>A
NM_001276697.1:c.-17G>A
NM_001276698.1:c.-17G>A
NM_001276699.1:c.-17G>A
NM_001276760.1:c.344G>A
NM_001276761.1:c.344G>A
NM_001276695.2:c.344G>A
NM_001276696.2:c.344G>A
NM_001276697.2:c.-17G>A
NM_001276698.2:c.-17G>A
NM_001276699.2:c.-17G>A
NM_001276760.2:c.344G>A
NM_001276761.2:c.344G>A
NM_000546.6:c.461G>A
NM_001126112.3:c.461G>A
NM_001126113.3:c.461G>A
NM_001126114.3:c.461G>A
NM_001126115.2:c.65G>A
NM_001126116.2:c.65G>A
NM_001126117.2:c.65G>A
NM_001126118.2:c.344G>A
NM_001276695.3:c.344G>A
NM_001276696.3:c.344G>A
NM_001276697.3:c.-17G>A
NM_001276698.3:c.-17G>A
NM_001276699.3:c.-17G>A
NM_001276760.3:c.344G>A
NM_001276761.3:c.344G>A
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Uncertain Significance

Met criteria codes 4
PM2_Supporting BS2_Supporting PP3_Moderate BS3_Supporting
Not Met criteria codes 16
PP4 PP1 PM3 PM1 PM5 PM6 BS4 BS1 BP2 BP4 BP5 PS2 PS4 PS3 PS1 BA1

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 2.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6:c.461G>A variant in TP53 is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 154 (p.Gly154Asp). This variant received a total of 0.5 points in 1 proband. (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal data contributor). This variant has an allele frequency of 0.000001859 (3/1614164 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_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). Computational predictor scores (BayesDel = 0.2733; 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). In summary, this variant meets the criteria to be classified as variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, PM2_supporting, BS3_Supporting, PP3_moderate. (Bayesian Points: 1; VCEP specifications version 2.2; 2/6/2025).
Met criteria codes
PM2_Supporting
This variant has an allele frequency of 0.000001859 (3/1614164 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
BS2_Supporting
This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Internal lab contributor).
PP3_Moderate
Computational predictor scores (BayesDel = 0.2733; 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).
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).
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
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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).
PM5
Five different missense variants (c.460G>T, p.Gly154Cys; c.460G>C, p.Gly154Arg; c.460G>A, p.Gly154Ser; c.461G>C, p.Gly154Ala; c.461G>T, p.Gly154Val) in the same codon have been reported (ClinVar Variation IDs: 1741887, 482229, 133284, 2840669, 651769). 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).
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
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
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
BP5
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
PS4
This variant received a total of 0.5 points in 1 proband. (PS4 not met; Internal lab contributors).
PS3
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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