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 label mismatch: TP53 vs undefined
  • 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.640C>T (p.His214Tyr)

CA397840049

1053808 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 5882f7fd-563a-4054-b5b9-d1a2a7c8daac
Approved on: 2025-06-05
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.640C>T
NM_000546.6(TP53):c.640C>T (p.His214Tyr)
NC_000017.11:g.7674891G>A
CM000679.2:g.7674891G>A
NC_000017.10:g.7578209G>A
CM000679.1:g.7578209G>A
NC_000017.9:g.7518934G>A
NG_017013.2:g.17660C>T
ENST00000503591.2:c.640C>T
ENST00000508793.6:c.640C>T
ENST00000509690.6:c.244C>T
ENST00000514944.6:c.361C>T
ENST00000604348.6:c.619C>T
ENST00000269305.9:c.640C>T
ENST00000269305.8:c.640C>T
ENST00000359597.8:c.640C>T
ENST00000413465.6:c.640C>T
ENST00000420246.6:c.640C>T
ENST00000445888.6:c.640C>T
ENST00000455263.6:c.640C>T
ENST00000504290.5:c.244C>T
ENST00000504937.5:c.244C>T
ENST00000505014.5:n.896C>T
ENST00000509690.5:c.244C>T
ENST00000510385.5:c.244C>T
ENST00000514944.5:c.361C>T
ENST00000574684.1:n.67+162C>T
ENST00000610292.4:c.523C>T
ENST00000610538.4:c.523C>T
ENST00000610623.4:c.163C>T
ENST00000615910.4:c.607C>T
ENST00000617185.4:c.640C>T
ENST00000618944.4:c.163C>T
ENST00000619186.4:c.163C>T
ENST00000619485.4:c.523C>T
ENST00000620739.4:c.523C>T
ENST00000622645.4:c.523C>T
ENST00000635293.1:c.523C>T
NM_000546.5:c.640C>T
NM_001126112.2:c.640C>T
NM_001126113.2:c.640C>T
NM_001126114.2:c.640C>T
NM_001126115.1:c.244C>T
NM_001126116.1:c.244C>T
NM_001126117.1:c.244C>T
NM_001126118.1:c.523C>T
NM_001276695.1:c.523C>T
NM_001276696.1:c.523C>T
NM_001276697.1:c.163C>T
NM_001276698.1:c.163C>T
NM_001276699.1:c.163C>T
NM_001276760.1:c.523C>T
NM_001276761.1:c.523C>T
NM_001276695.2:c.523C>T
NM_001276696.2:c.523C>T
NM_001276697.2:c.163C>T
NM_001276698.2:c.163C>T
NM_001276699.2:c.163C>T
NM_001276760.2:c.523C>T
NM_001276761.2:c.523C>T
NM_001126112.3:c.640C>T
NM_001126113.3:c.640C>T
NM_001126114.3:c.640C>T
NM_001126115.2:c.244C>T
NM_001126116.2:c.244C>T
NM_001126117.2:c.244C>T
NM_001126118.2:c.523C>T
NM_001276695.3:c.523C>T
NM_001276696.3:c.523C>T
NM_001276697.3:c.163C>T
NM_001276698.3:c.163C>T
NM_001276699.3:c.163C>T
NM_001276760.3:c.523C>T
NM_001276761.3:c.523C>T
More

Uncertain Significance

Met criteria codes 5
PP4 PP3 BS3_Supporting PM2_Supporting PM5
Not Met criteria codes 12
PP1 BS2 BS4 BS1 BP2 BP4 PS4 PS2 PS3 PS1 BA1 PM1

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.640C>T variant in TP53 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 214 (p.His214Tyr). 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; PMID: 36091175, Internal lab 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, Internal lab contributor). 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 retained growth suppression activity indicating that this variant does not impact protein function. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.188725; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Computational predictor scores (BayesDel = 0.188725; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant(c.641A>G, p.His214Arg) (ClinVar Variation ID: 376615), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). In summary, this variant meets the criteria to be classified as variant of uncertain clinical significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PP3, PP4, PM2_Supporting, PM5, BS3_Supporting. (Bayesian Points: 4; VCEP specifications version 2.3; date of approval)
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).
PP3
Computational predictor scores (BayesDel = 0.188725; Align GVGD = Class C35) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).
BS3_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. (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PM5
Another missense variant(c.641A>G, p.His214Arg) (ClinVar Variation ID: 376615), in the same codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5).
Not Met criteria codes
PP1
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
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
BP4
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; PMID: 36091175, Internal lab contributors).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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