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]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000546.6(TP53):c.105G>T (p.Leu35Phe)

CA000025

12371 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b73a437c-26a5-4491-8b92-edbe32570d9e
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

NM_000546.6:c.105G>T
NM_000546.6(TP53):c.105G>T (p.Leu35Phe)
NC_000017.11:g.7676264C>A
CM000679.2:g.7676264C>A
NC_000017.10:g.7579582C>A
CM000679.1:g.7579582C>A
NC_000017.9:g.7520307C>A
NG_017013.2:g.16287G>T
ENST00000503591.2:c.105G>T
ENST00000508793.6:c.105G>T
ENST00000509690.6:c.-21-1028G>T
ENST00000514944.6:c.96+118G>T
ENST00000604348.6:c.105G>T
ENST00000269305.9:c.105G>T
ENST00000269305.8:c.105G>T
ENST00000359597.8:c.105G>T
ENST00000413465.6:c.105G>T
ENST00000420246.6:c.105G>T
ENST00000445888.6:c.105G>T
ENST00000455263.6:c.105G>T
ENST00000503591.1:c.105G>T
ENST00000505014.5:n.361G>T
ENST00000508793.5:c.105G>T
ENST00000509690.5:c.-21-1028G>T
ENST00000514944.5:c.96+118G>T
ENST00000604348.5:c.105G>T
ENST00000610292.4:c.-13G>T
ENST00000610538.4:c.-13G>T
ENST00000615910.4:c.105G>T
ENST00000617185.4:c.105G>T
ENST00000619485.4:c.-13G>T
ENST00000620739.4:c.-13G>T
ENST00000622645.4:c.-13G>T
ENST00000635293.1:c.-13G>T
NM_000546.5:c.105G>T
NM_001126112.2:c.105G>T
NM_001126113.2:c.105G>T
NM_001126114.2:c.105G>T
NM_001126118.1:c.-13G>T
NM_001276695.1:c.-13G>T
NM_001276696.1:c.-13G>T
NM_001276760.1:c.-13G>T
NM_001276761.1:c.-13G>T
NM_001276695.2:c.-13G>T
NM_001276696.2:c.-13G>T
NM_001276760.2:c.-13G>T
NM_001276761.2:c.-13G>T
NM_001126112.3:c.105G>T
NM_001126113.3:c.105G>T
NM_001126114.3:c.105G>T
NM_001126118.2:c.-13G>T
NM_001276695.3:c.-13G>T
NM_001276696.3:c.-13G>T
NM_001276760.3:c.-13G>T
NM_001276761.3:c.-13G>T

Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting
Not Met criteria codes 14
PM1 PM5 PS2 PS4 PS3 PS1 BA1 PP1 PP4 PP3 BS2 BS4 BS3 BS1

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.105G>T variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = -0.078; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests there is no impact on the native site, and following expert review the variant is considered to have no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Variant of Uncertain Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BP4_Moderate. (Bayesian Points: -1; VCEP specifications version 2.0; date of approval)
Met criteria codes
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.078; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. Although SpliceAI predicts a weak potential splice effect, expert review suggests there is no impact on the native site, and following expert review the variant is considered to have no impact on splicing. (BP4_Moderate)
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
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
Another missense variant(c.103T>A, p.Leu35Met) in the same codon has been reported ( ClinVar Variation ID: 406609). However, this variant has not yet been curated to determine if it would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
The same amino acid change, resulting from a different nucleotide change (c.105G>C), has been reported (ClinVar Variation ID: 142562). However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PS1 not met).
BA1
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
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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Code not applied at PP3 is applied
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.