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.364G>A (p.Val122Met)

CA000134

141101 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b798ce06-59db-49cb-9737-d4dd3180f978
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.364G>A
NM_000546.5(TP53):c.364G>A (p.Val122Met)
NC_000017.11:g.7676005C>T
CM000679.2:g.7676005C>T
NC_000017.10:g.7579323C>T
CM000679.1:g.7579323C>T
NC_000017.9:g.7520048C>T
NG_017013.2:g.16546G>A
ENST00000503591.2:c.364G>A
ENST00000508793.6:c.364G>A
ENST00000509690.6:c.-21-769G>A
ENST00000514944.6:c.96+377G>A
ENST00000604348.6:c.364G>A
ENST00000269305.9:c.364G>A
ENST00000269305.8:c.364G>A
ENST00000359597.8:c.364G>A
ENST00000413465.6:c.364G>A
ENST00000420246.6:c.364G>A
ENST00000445888.6:c.364G>A
ENST00000455263.6:c.364G>A
ENST00000503591.1:c.364G>A
ENST00000505014.5:n.620G>A
ENST00000508793.5:c.364G>A
ENST00000509690.5:c.-21-769G>A
ENST00000514944.5:c.96+377G>A
ENST00000604348.5:c.364G>A
ENST00000610292.4:c.247G>A
ENST00000610538.4:c.247G>A
ENST00000615910.4:c.340+20G>A
ENST00000617185.4:c.364G>A
ENST00000619485.4:c.247G>A
ENST00000620739.4:c.247G>A
ENST00000622645.4:c.247G>A
ENST00000635293.1:c.247G>A
NM_001126112.2:c.364G>A
NM_001126113.2:c.364G>A
NM_001126114.2:c.364G>A
NM_001126118.1:c.247G>A
NM_001276695.1:c.247G>A
NM_001276696.1:c.247G>A
NM_001276760.1:c.247G>A
NM_001276761.1:c.247G>A
NM_001276695.2:c.247G>A
NM_001276696.2:c.247G>A
NM_001276760.2:c.247G>A
NM_001276761.2:c.247G>A
NM_000546.6:c.364G>A
NM_001126112.3:c.364G>A
NM_001126113.3:c.364G>A
NM_001126114.3:c.364G>A
NM_001126118.2:c.247G>A
NM_001276695.3:c.247G>A
NM_001276696.3:c.247G>A
NM_001276760.3:c.247G>A
NM_001276761.3:c.247G>A
More

Likely Benign

Met criteria codes 4
BP4 BS3_Supporting BS2_Supporting PM2_Supporting
Not Met criteria codes 14
BA1 BS4 BS1 BP2 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM1 PM5 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 2.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.364G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 122 (p.Val122Met). 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: Invitae). This variant has an allele frequency of 0.000001695 (2/1180034 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). 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 score (BayesDel = 0.134118) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 2.1; 1/16/2025).
Met criteria codes
BP4
Computational predictor score (BayesDel = 0.134118) is below the recommended threshold (BayesDel < 0.16), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4).
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).
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: Invitae).
PM2_Supporting
This variant has an allele frequency of 0.000001695 (2/1180034 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).
Not Met criteria codes
BA1
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
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 point across 1 unrelated proband. [However, PS4 cannot be (PS4 not met; Internal lab contributor: Invitae).
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
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
PP3
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
2 different missense variants (p.Val122Ala and p.Val122Leu) in the same codon have been reported (ClinVar Variation IDs: 1465964, 2121740). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 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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