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_000546.5(TP53):c.517G>A (p.Val173Met)

CA10577579

233951 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 29aaaea7-f2a2-441a-911c-111485dd6b50
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.517G>A
NM_000546.5(TP53):c.517G>A (p.Val173Met)
NC_000017.11:g.7675095C>T
CM000679.2:g.7675095C>T
NC_000017.10:g.7578413C>T
CM000679.1:g.7578413C>T
NC_000017.9:g.7519138C>T
NG_017013.2:g.17456G>A
ENST00000503591.2:c.517G>A
ENST00000508793.6:c.517G>A
ENST00000509690.6:c.121G>A
ENST00000514944.6:c.238G>A
ENST00000604348.6:c.496G>A
ENST00000269305.9:c.517G>A
ENST00000269305.8:c.517G>A
ENST00000359597.8:c.517G>A
ENST00000413465.6:c.517G>A
ENST00000420246.6:c.517G>A
ENST00000445888.6:c.517G>A
ENST00000455263.6:c.517G>A
ENST00000504290.5:c.121G>A
ENST00000504937.5:c.121G>A
ENST00000505014.5:n.773G>A
ENST00000509690.5:c.121G>A
ENST00000510385.5:c.121G>A
ENST00000514944.5:c.238G>A
ENST00000574684.1:n.25G>A
ENST00000610292.4:c.400G>A
ENST00000610538.4:c.400G>A
ENST00000610623.4:c.40G>A
ENST00000615910.4:c.484G>A
ENST00000617185.4:c.517G>A
ENST00000618944.4:c.40G>A
ENST00000619186.4:c.40G>A
ENST00000619485.4:c.400G>A
ENST00000620739.4:c.400G>A
ENST00000622645.4:c.400G>A
ENST00000635293.1:c.400G>A
NM_001126112.2:c.517G>A
NM_001126113.2:c.517G>A
NM_001126114.2:c.517G>A
NM_001126115.1:c.121G>A
NM_001126116.1:c.121G>A
NM_001126117.1:c.121G>A
NM_001126118.1:c.400G>A
NM_001276695.1:c.400G>A
NM_001276696.1:c.400G>A
NM_001276697.1:c.40G>A
NM_001276698.1:c.40G>A
NM_001276699.1:c.40G>A
NM_001276760.1:c.400G>A
NM_001276761.1:c.400G>A
NM_001276695.2:c.400G>A
NM_001276696.2:c.400G>A
NM_001276697.2:c.40G>A
NM_001276698.2:c.40G>A
NM_001276699.2:c.40G>A
NM_001276760.2:c.400G>A
NM_001276761.2:c.400G>A
NM_000546.6:c.517G>A
NM_001126112.3:c.517G>A
NM_001126113.3:c.517G>A
NM_001126114.3:c.517G>A
NM_001126115.2:c.121G>A
NM_001126116.2:c.121G>A
NM_001126117.2:c.121G>A
NM_001126118.2:c.400G>A
NM_001276695.3:c.400G>A
NM_001276696.3:c.400G>A
NM_001276697.3:c.40G>A
NM_001276698.3:c.40G>A
NM_001276699.3:c.40G>A
NM_001276760.3:c.400G>A
NM_001276761.3:c.400G>A
More

Pathogenic

Met criteria codes 5
PS3 PP4_Moderate PM1 PM2_Supporting PS4_Supporting
Not Met criteria codes 12
PS1 PS2 BP4 BA1 PP1 PP3 PVS1 PM5 BS2 BS4 BS1 BS3

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.517G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 173 (p.Val173Met). This variant has been reported in a proband meeting Classic criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID16494995). 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, SCV000278424.6). This variant has an allele frequency of 0.000001695 (2/1180054 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). This variant has 27 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 (PM1, ≥ 10 somatic occurrences, PMID: 30311369). In vitro assays performed in yeast and 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). 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: PS4_Supporting, PP4_Moderate, PM2_Supporting, PM1, PS3. (Bayesian Points: 10; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PS3
In vitro assays performed in yeast and 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).
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, SCV000278424.6).
PM1
This variant has 27 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 (PM1; ≥ 10 somatic occurrences, PMID: 30311369).
PM2_Supporting
This variant has an allele frequency of 0.000001695 (2/1180054 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).
PS4_Supporting
This variant has been reported in a proband meeting Classic criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID16494995).
Not Met criteria codes
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
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).
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).
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
4 different missense variants (p.Val173Leu, p.Val173Glu, p.Val173Ala, p.Val173Gly) in the same codon have been reported (ClinVar Variation IDs 1910599, 363548, 362896, 362895). 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).
BS2
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
Curation History
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