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.149T>C (p.Ile50Thr)

CA337284

216464 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: dfaea420-dc78-42fc-8466-b64b8fbcf7ed
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.6:c.149T>C
NM_000546.6(TP53):c.149T>C (p.Ile50Thr)
NC_000017.11:g.7676220A>G
CM000679.2:g.7676220A>G
NC_000017.10:g.7579538A>G
CM000679.1:g.7579538A>G
NC_000017.9:g.7520263A>G
NG_017013.2:g.16331T>C
ENST00000503591.2:c.149T>C
ENST00000508793.6:c.149T>C
ENST00000509690.6:c.-21-984T>C
ENST00000514944.6:c.96+162T>C
ENST00000604348.6:c.149T>C
ENST00000269305.9:c.149T>C
ENST00000269305.8:c.149T>C
ENST00000359597.8:c.149T>C
ENST00000413465.6:c.149T>C
ENST00000420246.6:c.149T>C
ENST00000445888.6:c.149T>C
ENST00000455263.6:c.149T>C
ENST00000503591.1:c.149T>C
ENST00000505014.5:n.405T>C
ENST00000508793.5:c.149T>C
ENST00000509690.5:c.-21-984T>C
ENST00000514944.5:c.96+162T>C
ENST00000604348.5:c.149T>C
ENST00000610292.4:c.32T>C
ENST00000610538.4:c.32T>C
ENST00000615910.4:c.149T>C
ENST00000617185.4:c.149T>C
ENST00000619485.4:c.32T>C
ENST00000620739.4:c.32T>C
ENST00000622645.4:c.32T>C
ENST00000635293.1:c.32T>C
NM_000546.5:c.149T>C
NM_001126112.2:c.149T>C
NM_001126113.2:c.149T>C
NM_001126114.2:c.149T>C
NM_001126118.1:c.32T>C
NM_001276695.1:c.32T>C
NM_001276696.1:c.32T>C
NM_001276760.1:c.32T>C
NM_001276761.1:c.32T>C
NM_001276695.2:c.32T>C
NM_001276696.2:c.32T>C
NM_001276760.2:c.32T>C
NM_001276761.2:c.32T>C
NM_001126112.3:c.149T>C
NM_001126113.3:c.149T>C
NM_001126114.3:c.149T>C
NM_001126118.2:c.32T>C
NM_001276695.3:c.32T>C
NM_001276696.3:c.32T>C
NM_001276760.3:c.32T>C
NM_001276761.3:c.32T>C
More

Likely Benign

Met criteria codes 4
PP4 BS2 PM2_Supporting BP4
Not Met criteria codes 12
PS2 PS4 PS3 PS1 PP1 PP3 PM1 PM5 BS4 BS3 BS1 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 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.149T>C variant in TP53 is a missense variant predicted to cause substitution of Isoleucine by Threonine at amino acid 50 (p.Ile50Thr). This variant has been observed in 4-7 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_Moderate; Internal lab contributor: LabCorp Genetics). 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, Internal lab contributor: LabCorp Genetics). This variant has an allele frequency of 0.000001239 (2/1614026 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) 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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.0655; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). 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_Moderate, PP4, PM2_Supporting, BP4_Moderate. (Bayesian Points: -2; VCEP specifications version 2.1.0; 1/16/2025)
Met criteria codes
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, Internal lab contributor: LabCorp Genetics).
BS2
BS2_MODERATE This variant has been observed in 4-7 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_Moderate; Internal lab contributor: LabCorp Genetics).
PM2_Supporting
This variant has an allele frequency of 0.000001239 (2/1614026 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
BP4
BP4_MODERATE. Computational predictor scores (BayesDel = -0.0655; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644).
PS1
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.Ile50Asn and p..Ile50Leu) in the same codon have been reported. 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).
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644).
BS1
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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