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_000546.6(TP53):c.589G>A (p.Val197Met)

CA000285

188060 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 71db6d7d-97cf-48a7-9d09-d4b48fdbbc5d
Approved on: 2025-12-05
Published on: 2025-12-05

HGVS expressions

NM_000546.6:c.589G>A
NM_000546.6(TP53):c.589G>A (p.Val197Met)
NC_000017.11:g.7674942C>T
CM000679.2:g.7674942C>T
NC_000017.10:g.7578260C>T
CM000679.1:g.7578260C>T
NC_000017.9:g.7518985C>T
NG_017013.2:g.17609G>A
ENST00000503591.2:c.589G>A
ENST00000508793.6:c.589G>A
ENST00000509690.6:c.193G>A
ENST00000514944.6:c.310G>A
ENST00000604348.6:c.568G>A
ENST00000269305.9:c.589G>A
ENST00000269305.8:c.589G>A
ENST00000359597.8:c.589G>A
ENST00000413465.6:c.589G>A
ENST00000420246.6:c.589G>A
ENST00000445888.6:c.589G>A
ENST00000455263.6:c.589G>A
ENST00000504290.5:c.193G>A
ENST00000504937.5:c.193G>A
ENST00000505014.5:n.845G>A
ENST00000509690.5:c.193G>A
ENST00000510385.5:c.193G>A
ENST00000514944.5:c.310G>A
ENST00000574684.1:n.67+111G>A
ENST00000610292.4:c.472G>A
ENST00000610538.4:c.472G>A
ENST00000610623.4:c.112G>A
ENST00000615910.4:c.556G>A
ENST00000617185.4:c.589G>A
ENST00000618944.4:c.112G>A
ENST00000619186.4:c.112G>A
ENST00000619485.4:c.472G>A
ENST00000620739.4:c.472G>A
ENST00000622645.4:c.472G>A
ENST00000635293.1:c.472G>A
NM_000546.5:c.589G>A
NM_001126112.2:c.589G>A
NM_001126113.2:c.589G>A
NM_001126114.2:c.589G>A
NM_001126115.1:c.193G>A
NM_001126116.1:c.193G>A
NM_001126117.1:c.193G>A
NM_001126118.1:c.472G>A
NM_001276695.1:c.472G>A
NM_001276696.1:c.472G>A
NM_001276697.1:c.112G>A
NM_001276698.1:c.112G>A
NM_001276699.1:c.112G>A
NM_001276760.1:c.472G>A
NM_001276761.1:c.472G>A
NM_001276695.2:c.472G>A
NM_001276696.2:c.472G>A
NM_001276697.2:c.112G>A
NM_001276698.2:c.112G>A
NM_001276699.2:c.112G>A
NM_001276760.2:c.472G>A
NM_001276761.2:c.472G>A
NM_001126112.3:c.589G>A
NM_001126113.3:c.589G>A
NM_001126114.3:c.589G>A
NM_001126115.2:c.193G>A
NM_001126116.2:c.193G>A
NM_001126117.2:c.193G>A
NM_001126118.2:c.472G>A
NM_001276695.3:c.472G>A
NM_001276696.3:c.472G>A
NM_001276697.3:c.112G>A
NM_001276698.3:c.112G>A
NM_001276699.3:c.112G>A
NM_001276760.3:c.472G>A
NM_001276761.3:c.472G>A
More

Likely Pathogenic

Met criteria codes 5
PS4_Supporting PM1_Supporting PP4 PS3_Moderate PM2_Supporting
Not Met criteria codes 6
BA1 BS3 BS1 BP4 PS1 PP3

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 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6:c.589G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 197 (p.Val197Met). This variant has been reported in 1 family meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, ClinVar SCV001186711.5, Internal lab contributors). 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). This variant has three 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 (2–9 somatic occurrences; PMID: 30311369) (PM1_Supporting). 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_Supporting, PP4, PM2_Supporting, PS3_Moderate, PM1_Supporting (Bayesian Points: 6; VCEP specifications version 2.3).
Met criteria codes
PS4_Supporting
This variant has been reported in 1 family meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors).
PM1_Supporting
This variant has 3 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 (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).
PP4
At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, ClinVar SCV001186711.5, Internal lab contributors).
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).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (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
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
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, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PS1
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, SpliceAI predicts that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
Curation History
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