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.641A>T (p.His214Leu)

CA16603036

376616 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cf612f4d-8714-4890-adea-2a2dc1ea00b9
Approved on: 2025-05-07
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.641A>T
NM_000546.6(TP53):c.641A>T (p.His214Leu)
NC_000017.11:g.7674890T>A
CM000679.2:g.7674890T>A
NC_000017.10:g.7578208T>A
CM000679.1:g.7578208T>A
NC_000017.9:g.7518933T>A
NG_017013.2:g.17661A>T
ENST00000503591.2:c.641A>T
ENST00000508793.6:c.641A>T
ENST00000509690.6:c.245A>T
ENST00000514944.6:c.362A>T
ENST00000604348.6:c.620A>T
ENST00000269305.9:c.641A>T
ENST00000269305.8:c.641A>T
ENST00000359597.8:c.641A>T
ENST00000413465.6:c.641A>T
ENST00000420246.6:c.641A>T
ENST00000445888.6:c.641A>T
ENST00000455263.6:c.641A>T
ENST00000504290.5:c.245A>T
ENST00000504937.5:c.245A>T
ENST00000505014.5:n.897A>T
ENST00000509690.5:c.245A>T
ENST00000510385.5:c.245A>T
ENST00000514944.5:c.362A>T
ENST00000574684.1:n.67+163A>T
ENST00000610292.4:c.524A>T
ENST00000610538.4:c.524A>T
ENST00000610623.4:c.164A>T
ENST00000615910.4:c.608A>T
ENST00000617185.4:c.641A>T
ENST00000618944.4:c.164A>T
ENST00000619186.4:c.164A>T
ENST00000619485.4:c.524A>T
ENST00000620739.4:c.524A>T
ENST00000622645.4:c.524A>T
ENST00000635293.1:c.524A>T
NM_000546.5:c.641A>T
NM_001126112.2:c.641A>T
NM_001126113.2:c.641A>T
NM_001126114.2:c.641A>T
NM_001126115.1:c.245A>T
NM_001126116.1:c.245A>T
NM_001126117.1:c.245A>T
NM_001126118.1:c.524A>T
NM_001276695.1:c.524A>T
NM_001276696.1:c.524A>T
NM_001276697.1:c.164A>T
NM_001276698.1:c.164A>T
NM_001276699.1:c.164A>T
NM_001276760.1:c.524A>T
NM_001276761.1:c.524A>T
NM_001276695.2:c.524A>T
NM_001276696.2:c.524A>T
NM_001276697.2:c.164A>T
NM_001276698.2:c.164A>T
NM_001276699.2:c.164A>T
NM_001276760.2:c.524A>T
NM_001276761.2:c.524A>T
NM_001126112.3:c.641A>T
NM_001126113.3:c.641A>T
NM_001126114.3:c.641A>T
NM_001126115.2:c.245A>T
NM_001126116.2:c.245A>T
NM_001126117.2:c.245A>T
NM_001126118.2:c.524A>T
NM_001276695.3:c.524A>T
NM_001276696.3:c.524A>T
NM_001276697.3:c.164A>T
NM_001276698.3:c.164A>T
NM_001276699.3:c.164A>T
NM_001276760.3:c.524A>T
NM_001276761.3:c.524A>T
More

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PS3 PM5 PM1_Supporting PP3
Not Met criteria codes 11
BS4 BS3 BS1 BS2 BP4 PS2 PS4 PS1 BA1 PP4 PP1

Evidence Links 3

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.641A>T variant in TP53 is a missense variant predicted to cause substitution of histidine by leucine at amino acid 214 (p.His214Leu). To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Computational predictor scores (BayesDel = 0.323206; 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. In addition, missense variant (c.640C>T, p.His214Tyr) (ClinVar Variation ID 1053808) in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP's specifications. (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP3, PM1_Supporting, PM2_Supporting, PM5. (Bayesian Points: 9; VCEP specifications version 2.3)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PS3
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965).
Non functional (14.05%) PubMed:12826609
LOF PubMed:30224644
LOF PubMed:29979965
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. In addition, missense variant (c.640C>T, p.His214Tyr) (ClinVar Variation ID 1053808) in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP's specifications. (PM5).
PM1_Supporting
This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).
PP3
Computational predictor scores (BayesDel = 0.323206; 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).
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
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
BS2
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
To our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met).
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
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
Curation History
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