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.656C>T (p.Pro219Leu)

CA397839907

826488 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 61d9fc98-9d3c-4239-88a3-9dfad2491b5e
Approved on: 2026-02-05
Published on: 2026-02-10

HGVS expressions

NM_000546.6:c.656C>T
NM_000546.6(TP53):c.656C>T (p.Pro219Leu)
NC_000017.11:g.7674875G>A
CM000679.2:g.7674875G>A
NC_000017.10:g.7578193G>A
CM000679.1:g.7578193G>A
NC_000017.9:g.7518918G>A
NG_017013.2:g.17676C>T
ENST00000503591.2:c.656C>T
ENST00000508793.6:c.656C>T
ENST00000509690.6:c.260C>T
ENST00000514944.6:c.377C>T
ENST00000604348.6:c.635C>T
ENST00000269305.9:c.656C>T
ENST00000269305.8:c.656C>T
ENST00000359597.8:c.656C>T
ENST00000413465.6:c.656C>T
ENST00000420246.6:c.656C>T
ENST00000445888.6:c.656C>T
ENST00000455263.6:c.656C>T
ENST00000504290.5:c.260C>T
ENST00000504937.5:c.260C>T
ENST00000505014.5:n.912C>T
ENST00000509690.5:c.260C>T
ENST00000510385.5:c.260C>T
ENST00000514944.5:c.377C>T
ENST00000574684.1:n.67+178C>T
ENST00000610292.4:c.539C>T
ENST00000610538.4:c.539C>T
ENST00000610623.4:c.179C>T
ENST00000615910.4:c.623C>T
ENST00000617185.4:c.656C>T
ENST00000618944.4:c.179C>T
ENST00000619186.4:c.179C>T
ENST00000619485.4:c.539C>T
ENST00000620739.4:c.539C>T
ENST00000622645.4:c.539C>T
ENST00000635293.1:c.539C>T
NM_000546.5:c.656C>T
NM_001126112.2:c.656C>T
NM_001126113.2:c.656C>T
NM_001126114.2:c.656C>T
NM_001126115.1:c.260C>T
NM_001126116.1:c.260C>T
NM_001126117.1:c.260C>T
NM_001126118.1:c.539C>T
NM_001276695.1:c.539C>T
NM_001276696.1:c.539C>T
NM_001276697.1:c.179C>T
NM_001276698.1:c.179C>T
NM_001276699.1:c.179C>T
NM_001276760.1:c.539C>T
NM_001276761.1:c.539C>T
NM_001276695.2:c.539C>T
NM_001276696.2:c.539C>T
NM_001276697.2:c.179C>T
NM_001276698.2:c.179C>T
NM_001276699.2:c.179C>T
NM_001276760.2:c.539C>T
NM_001276761.2:c.539C>T
NM_001126112.3:c.656C>T
NM_001126113.3:c.656C>T
NM_001126114.3:c.656C>T
NM_001126115.2:c.260C>T
NM_001126116.2:c.260C>T
NM_001126117.2:c.260C>T
NM_001126118.2:c.539C>T
NM_001276695.3:c.539C>T
NM_001276696.3:c.539C>T
NM_001276697.3:c.179C>T
NM_001276698.3:c.179C>T
NM_001276699.3:c.179C>T
NM_001276760.3:c.539C>T
NM_001276761.3:c.539C>T
More

Uncertain Significance

Met criteria codes 2
PP3_Moderate PM2_Supporting
Not Met criteria codes 14
BP4 BS2 BS4 BS3 BS1 PP4 PP1 PS2 PS4 PS3 PS1 PM1 PM5 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 2.4.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.656C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 219 (p.Pro219Leu). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614106 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (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, 39774325, 29979965, 30224644). Computational predictor scores (BayesDel = 0.585695; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as variant of uncertain signficance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PP3_Moderate. (Bayesian Points: 3; VCEP specifications version 2.4)
Met criteria codes
PP3_Moderate
Computational predictor scores (BayesDel = 0.585695; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).
PM2_Supporting
This variant has an allele frequency of 6.195e-7 (1/1614106 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting).
Not Met criteria codes
BP4
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, 39774325, 29979965, 30224644)
BS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors).
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, 39774325, 29979965, 30224644)
PS1
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
3 different missense variants (p.Pro219Ala, p.Pro219Thr, p.Pro219Ser) in the same codon have been reported (ClinVar Variation IDs: 2850523, 2758381, 245673). 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). P219L = 98 P219A = 27 (VUS ClinVar) P219T = 38 (VUS in ClinVar) P219S = 38 (VUS in ClinVar) P219R = 103 (VUS ClinVar)
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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