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 computer assertion could be determined for this classification!

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

CA000024

142562 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 9f61138a-40be-4434-b6e0-cba991e23049
Approved on: 2024-09-06
Published on: 2024-09-06

HGVS expressions

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

Likely Benign

Met criteria codes 4
BP4 PM2_Supporting BS3 BS2_Supporting
Not Met criteria codes 15
BP5 BP2 PS2 PS4 PS3 PS1 PM1 PM3 PM5 BA1 PP4 PP1 PP3 BS4 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>C variant in TP53 is a missense variant predicted to cause substitution of leucine by phenylalanine at amino acid 35 (p.Leu35Phe). This variant has been observed in 2-3 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_Supporting; Invitae). This variant has an allele frequency of 0.00001186 (14/1180022 alleles) in the European (Non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). 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). Computational predictor scores (BayesDel = -0.0784742; 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. 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 Significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024).
Met criteria codes
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.0784742; 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. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate)
PM2_Supporting
This variant has an allele frequency of 0.00001186 (14/1180022 alleles) in the European (Non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
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).
BS2_Supporting
This variant has been observed in 2-3 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_Supporting; Invitae).
Not Met criteria codes
BP5
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
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 across 1 proband (PS4 not met; Invitae).
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>T), (ClinVar Variation ID: 12371). 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).
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).
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
A different 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 evaluated).
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
PP3
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
Curation History
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