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.214C>G (p.Pro72Ala)

CA000070

142854 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3a7347e6-77f5-4cc5-a6d2-555e45cc238b
Approved on: 2025-02-06
Published on: 2025-02-07

HGVS expressions

NM_000546.5:c.214C>G
NM_000546.5(TP53):c.214C>G (p.Pro72Ala)
NC_000017.11:g.7676155G>C
CM000679.2:g.7676155G>C
NC_000017.10:g.7579473G>C
CM000679.1:g.7579473G>C
NC_000017.9:g.7520198G>C
NG_017013.2:g.16396C>G
ENST00000503591.2:c.214C>G
ENST00000508793.6:c.214C>G
ENST00000509690.6:c.-21-919C>G
ENST00000514944.6:c.96+227C>G
ENST00000604348.6:c.214C>G
ENST00000269305.9:c.214C>G
ENST00000269305.8:c.214C>G
ENST00000359597.8:c.214C>G
ENST00000413465.6:c.214C>G
ENST00000420246.6:c.214C>G
ENST00000445888.6:c.214C>G
ENST00000455263.6:c.214C>G
ENST00000503591.1:c.214C>G
ENST00000505014.5:n.470C>G
ENST00000508793.5:c.214C>G
ENST00000509690.5:c.-21-919C>G
ENST00000514944.5:c.96+227C>G
ENST00000604348.5:c.214C>G
ENST00000610292.4:c.97C>G
ENST00000610538.4:c.97C>G
ENST00000615910.4:c.214C>G
ENST00000617185.4:c.214C>G
ENST00000619485.4:c.97C>G
ENST00000620739.4:c.97C>G
ENST00000622645.4:c.97C>G
ENST00000635293.1:c.97C>G
NM_001126112.2:c.214C>G
NM_001126113.2:c.214C>G
NM_001126114.2:c.214C>G
NM_001126118.1:c.97C>G
NM_001276695.1:c.97C>G
NM_001276696.1:c.97C>G
NM_001276760.1:c.97C>G
NM_001276761.1:c.97C>G
NM_001276695.2:c.97C>G
NM_001276696.2:c.97C>G
NM_001276760.2:c.97C>G
NM_001276761.2:c.97C>G
NM_000546.6:c.214C>G
NM_001126112.3:c.214C>G
NM_001126113.3:c.214C>G
NM_001126114.3:c.214C>G
NM_001126118.2:c.97C>G
NM_001276695.3:c.97C>G
NM_001276696.3:c.97C>G
NM_001276760.3:c.97C>G
NM_001276761.3:c.97C>G
More

Likely Benign

Met criteria codes 2
BS2 BP4
Not Met criteria codes 19
PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2 BA1 PM6 PM2 PM3 PM1 PM5 BS4 BS3 BS1 BP2 BP1

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.214C>G variant in TP53 is a missense variant predicted to cause substitution of proline by alanine at amino acid 72 (p.Pro72Ala). This is a polymorphic residue (alternate nomenclature: p.Arg72). This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors). 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). 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, 30224644). Computational predictor scores (BayesDel = -0.215412; 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_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, BP4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.2; 2/6/2025)
Met criteria codes
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).
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.215412; 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_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
This variant received a total of 0.5 points in one individual. (PS4 not met; Internal lab contributors).
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
PP2
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v4.1.0 is 0.0001337 (6/44892 alleles) in the East Asian population (PM2, BS1, and BA1 are not met).
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).
PM5
10 different missense variants in the same codon have been reported (ClinVar Variation IDs: 2176025, 232750, 485023, 12351, 182953, 185120, 1786573, 3328172, 237944, 864652) although all are B/LB/VUS and none are suspicious for pathogenicity (PM5 not met).
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, 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
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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