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]
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  • 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_000546.5(TP53):c.145G>A (p.Asp49Asn)

CA000056

186363 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 919a92fa-b50b-4d78-ad70-26b081a7dc4d
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.145G>A
NM_000546.5(TP53):c.145G>A (p.Asp49Asn)
NC_000017.11:g.7676224C>T
CM000679.2:g.7676224C>T
NC_000017.10:g.7579542C>T
CM000679.1:g.7579542C>T
NC_000017.9:g.7520267C>T
NG_017013.2:g.16327G>A
ENST00000503591.2:c.145G>A
ENST00000508793.6:c.145G>A
ENST00000509690.6:c.-21-988G>A
ENST00000514944.6:c.96+158G>A
ENST00000604348.6:c.145G>A
ENST00000269305.9:c.145G>A
ENST00000269305.8:c.145G>A
ENST00000359597.8:c.145G>A
ENST00000413465.6:c.145G>A
ENST00000420246.6:c.145G>A
ENST00000445888.6:c.145G>A
ENST00000455263.6:c.145G>A
ENST00000503591.1:c.145G>A
ENST00000505014.5:n.401G>A
ENST00000508793.5:c.145G>A
ENST00000509690.5:c.-21-988G>A
ENST00000514944.5:c.96+158G>A
ENST00000604348.5:c.145G>A
ENST00000610292.4:c.28G>A
ENST00000610538.4:c.28G>A
ENST00000615910.4:c.145G>A
ENST00000617185.4:c.145G>A
ENST00000619485.4:c.28G>A
ENST00000620739.4:c.28G>A
ENST00000622645.4:c.28G>A
ENST00000635293.1:c.28G>A
NM_001126112.2:c.145G>A
NM_001126113.2:c.145G>A
NM_001126114.2:c.145G>A
NM_001126118.1:c.28G>A
NM_001276695.1:c.28G>A
NM_001276696.1:c.28G>A
NM_001276760.1:c.28G>A
NM_001276761.1:c.28G>A
NM_001276695.2:c.28G>A
NM_001276696.2:c.28G>A
NM_001276760.2:c.28G>A
NM_001276761.2:c.28G>A
NM_000546.6:c.145G>A
NM_001126112.3:c.145G>A
NM_001126113.3:c.145G>A
NM_001126114.3:c.145G>A
NM_001126118.2:c.28G>A
NM_001276695.3:c.28G>A
NM_001276696.3:c.28G>A
NM_001276760.3:c.28G>A
NM_001276761.3:c.28G>A

Benign

Met criteria codes 4
BS2 BS3 BP4 PM2_Supporting
Not Met criteria codes 10
BA1 BS4 BS1 PS2 PS1 PS3 PP4 PP1 PM1 PM5

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.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 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; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) 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 = -0.232; 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 Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
BS2
This variant has been observed in at least 8 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; ClinVar SCV: SCV000216702.6).
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 (PMIDs: 12826609, 29979965, 30224644) (BS3)
BP4
BP4_MODERATE APPLIED Computational predictor scores (BayesDel = -0.232; 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 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
BA1
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
PS2
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
PS3
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
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
4 different missense variants (c.147T>G, p.Asp49Glu; c.147T>A; p.Asp49Glu; c.146A>G, p.Asp49Gly; c.145G>C, p.Asp49His) in the same codon have been reported (ClinVar Variation IDs: 1506044, 1361888, 231133, 135948). However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
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