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.634T>A (p.Phe212Ile)

CA16620624

422414 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 316a4c4a-ff7a-4b9e-89e6-c92af23915b9
Approved on: 2026-02-05
Published on: 2026-02-10

HGVS expressions

NM_000546.6(TP53):c.634T>A (p.Phe212Ile)
NM_000546.6:c.634T>A
NC_000017.11:g.7674897A>T
CM000679.2:g.7674897A>T
NC_000017.10:g.7578215A>T
CM000679.1:g.7578215A>T
NC_000017.9:g.7518940A>T
NG_017013.2:g.17654T>A
ENST00000503591.2:c.634T>A
ENST00000508793.6:c.634T>A
ENST00000509690.6:c.238T>A
ENST00000514944.6:c.355T>A
ENST00000604348.6:c.613T>A
ENST00000269305.9:c.634T>A
ENST00000269305.8:c.634T>A
ENST00000359597.8:c.634T>A
ENST00000413465.6:c.634T>A
ENST00000420246.6:c.634T>A
ENST00000445888.6:c.634T>A
ENST00000455263.6:c.634T>A
ENST00000504290.5:c.238T>A
ENST00000504937.5:c.238T>A
ENST00000505014.5:n.890T>A
ENST00000509690.5:c.238T>A
ENST00000510385.5:c.238T>A
ENST00000514944.5:c.355T>A
ENST00000574684.1:n.67+156T>A
ENST00000610292.4:c.517T>A
ENST00000610538.4:c.517T>A
ENST00000610623.4:c.157T>A
ENST00000615910.4:c.601T>A
ENST00000617185.4:c.634T>A
ENST00000618944.4:c.157T>A
ENST00000619186.4:c.157T>A
ENST00000619485.4:c.517T>A
ENST00000620739.4:c.517T>A
ENST00000622645.4:c.517T>A
ENST00000635293.1:c.517T>A
NM_000546.5:c.634T>A
NM_001126112.2:c.634T>A
NM_001126113.2:c.634T>A
NM_001126114.2:c.634T>A
NM_001126115.1:c.238T>A
NM_001126116.1:c.238T>A
NM_001126117.1:c.238T>A
NM_001126118.1:c.517T>A
NM_001276695.1:c.517T>A
NM_001276696.1:c.517T>A
NM_001276697.1:c.157T>A
NM_001276698.1:c.157T>A
NM_001276699.1:c.157T>A
NM_001276760.1:c.517T>A
NM_001276761.1:c.517T>A
NM_001276695.2:c.517T>A
NM_001276696.2:c.517T>A
NM_001276697.2:c.157T>A
NM_001276698.2:c.157T>A
NM_001276699.2:c.157T>A
NM_001276760.2:c.517T>A
NM_001276761.2:c.517T>A
NM_001126112.3:c.634T>A
NM_001126113.3:c.634T>A
NM_001126114.3:c.634T>A
NM_001126115.2:c.238T>A
NM_001126116.2:c.238T>A
NM_001126117.2:c.238T>A
NM_001126118.2:c.517T>A
NM_001276695.3:c.517T>A
NM_001276696.3:c.517T>A
NM_001276697.3:c.157T>A
NM_001276698.3:c.157T>A
NM_001276699.3:c.157T>A
NM_001276760.3:c.517T>A
NM_001276761.3:c.517T>A
More

Uncertain Significance

Met criteria codes 3
PM2_Supporting BP4 PS4_Supporting
Not Met criteria codes 23
BA1 PS2 PS3 PS1 PP1 PP4 PP3 PP2 PM3 PM1 PM4 PM5 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP1 BP5 BP7 PVS1

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 2.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.634T>A variant in TP53 is a missense variant predicted to cause substitution of phenylalanine by isoleucine at amino acid 212 (p.Phe212Ile). This variant has been reported in 2 unrelated proband smeeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; 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 conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644). Computational predictor scores (BayesDel = -0.00674022; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as of uncertain significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, BP4, PM2_supporting. (Bayesian Points: 1; VCEP specifications version 2.4)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BP4
Computational predictor scores (BayesDel = -0.00674022; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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).
PS4_Supporting
This variant has been reported in 2 unrelated probandcsmeeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors).
Not Met criteria codes
BA1
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
PS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 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
PP4
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
PP2
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).
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 16007150, 29979965, 30224644).
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
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
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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