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_001126112.2(TP53):c.145G>C (p.Asp49His)

CA000057

135948 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3ae5f394-d710-4984-8d13-7c585ade67dc
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_001126112.2:c.145G>C
NM_001126112.2(TP53):c.145G>C (p.Asp49His)
NC_000017.11:g.7676224C>G
CM000679.2:g.7676224C>G
NC_000017.10:g.7579542C>G
CM000679.1:g.7579542C>G
NC_000017.9:g.7520267C>G
NG_017013.2:g.16327G>C
ENST00000503591.2:c.145G>C
ENST00000508793.6:c.145G>C
ENST00000509690.6:c.-21-988G>C
ENST00000514944.6:c.96+158G>C
ENST00000604348.6:c.145G>C
ENST00000269305.9:c.145G>C
ENST00000269305.8:c.145G>C
ENST00000359597.8:c.145G>C
ENST00000413465.6:c.145G>C
ENST00000420246.6:c.145G>C
ENST00000445888.6:c.145G>C
ENST00000455263.6:c.145G>C
ENST00000503591.1:c.145G>C
ENST00000505014.5:n.401G>C
ENST00000508793.5:c.145G>C
ENST00000509690.5:c.-21-988G>C
ENST00000514944.5:c.96+158G>C
ENST00000604348.5:c.145G>C
ENST00000610292.4:c.28G>C
ENST00000610538.4:c.28G>C
ENST00000615910.4:c.145G>C
ENST00000617185.4:c.145G>C
ENST00000619485.4:c.28G>C
ENST00000620739.4:c.28G>C
ENST00000622645.4:c.28G>C
ENST00000635293.1:c.28G>C
NM_000546.5:c.145G>C
NM_001126113.2:c.145G>C
NM_001126114.2:c.145G>C
NM_001126118.1:c.28G>C
NM_001276695.1:c.28G>C
NM_001276696.1:c.28G>C
NM_001276760.1:c.28G>C
NM_001276761.1:c.28G>C
NM_001276695.2:c.28G>C
NM_001276696.2:c.28G>C
NM_001276760.2:c.28G>C
NM_001276761.2:c.28G>C
NM_000546.6:c.145G>C
NM_001126112.3:c.145G>C
NM_001126113.3:c.145G>C
NM_001126114.3:c.145G>C
NM_001126118.2:c.28G>C
NM_001276695.3:c.28G>C
NM_001276696.3:c.28G>C
NM_001276760.3:c.28G>C
NM_001276761.3:c.28G>C
More

Benign

Met criteria codes 3
BS2_Supporting BS1 BP4
Not Met criteria codes 17
PM2 PM3 PM1 PM5 BA1 BS4 BS3 BP2 BP1 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PP2

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.145G>C variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by histidine at amino acid 49 (p.Asp49His). 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; Internal lab contributors). The filtering allele frequency is 0.0007696 in the East Asian population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1). In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644, 15489903, 12901974, 18199664). Computational predictor scores (BayesDel = -0.0307; Align GVGD Class 0) 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). This variant has been reported as a putative founder variant in the Japanese population (PMID: 27545002). 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_Supporting, BS1, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1.0; 1/16/2025)
Met criteria codes
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; Internal lab contributors). 3 female individuals cancer free by age 60 at Ambry.
BS1
The filtering allele frequency is 0.0007696 in the East Asian population in gnomAD v4.1.0, which is higher than the ClinGen TP53 VCEP threshold (≥0.0003 but <0.001) for BS1, and therefore meets this criterion (BS1).
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.0307; Align GVGD Class 0) 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).
Not Met criteria codes
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
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
Four different missense variants (c.147T>G (p.Asp49Glu); c.147T>A (p.Asp49Glu); c.146A>G (p.Asp49Gly); c.145G>A (p.Asp49Asn)) in the same codon have been reported (ClinVar Variation ID: 1506044, 1361888, 231133, 186363). However, one is curated as benign by the ClinGen TP53 VCEP, and the other variants have not yet been curated to determine if they 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
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 conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644, 15489903, 12901974, 18199664).
Variant disrupts the human replication protein A (RPA)-binding domain without compromising transactivation function PubMed:15489903
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
These evidence codes are not currently applicable for TP53 VCEP curations
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 points across dozens of unrelated probands (PS4 not met; PMIDs: 1565143, 27545002, 28902083, 29667044, 30287823, 33309985, 34863587, Internal lab contributors). Many cases were missing family history to fully assess potential point values.
PS3
In vitro assays performed in yeast and/or human cell lines showed conflicting results with respect to transactivation, growth suppression activity, and/or tetramer formation (PS3/BS3 not met; PMIDs: 12826609, 30224644, 15489903, 12901974, 18199664).
Variant disrupts the human replication protein A (RPA)-binding domain without compromising transactivation function PubMed:15489903
PS1
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
PP2
These evidence codes are not currently applicable for TP53 VCEP curations
Curation History
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.