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.188C>T (p.Ala63Val)

CA000063

182922 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ef9d90c6-8b7a-4989-9f0f-7bd7f52113b0
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_001126112.2:c.188C>T
NM_001126112.2(TP53):c.188C>T (p.Ala63Val)
NC_000017.11:g.7676181G>A
CM000679.2:g.7676181G>A
NC_000017.10:g.7579499G>A
CM000679.1:g.7579499G>A
NC_000017.9:g.7520224G>A
NG_017013.2:g.16370C>T
ENST00000503591.2:c.188C>T
ENST00000508793.6:c.188C>T
ENST00000509690.6:c.-21-945C>T
ENST00000514944.6:c.96+201C>T
ENST00000604348.6:c.188C>T
ENST00000269305.9:c.188C>T
ENST00000269305.8:c.188C>T
ENST00000359597.8:c.188C>T
ENST00000413465.6:c.188C>T
ENST00000420246.6:c.188C>T
ENST00000445888.6:c.188C>T
ENST00000455263.6:c.188C>T
ENST00000503591.1:c.188C>T
ENST00000505014.5:n.444C>T
ENST00000508793.5:c.188C>T
ENST00000509690.5:c.-21-945C>T
ENST00000514944.5:c.96+201C>T
ENST00000604348.5:c.188C>T
ENST00000610292.4:c.71C>T
ENST00000610538.4:c.71C>T
ENST00000615910.4:c.188C>T
ENST00000617185.4:c.188C>T
ENST00000619485.4:c.71C>T
ENST00000620739.4:c.71C>T
ENST00000622645.4:c.71C>T
ENST00000635293.1:c.71C>T
NM_000546.5:c.188C>T
NM_001126113.2:c.188C>T
NM_001126114.2:c.188C>T
NM_001126118.1:c.71C>T
NM_001276695.1:c.71C>T
NM_001276696.1:c.71C>T
NM_001276760.1:c.71C>T
NM_001276761.1:c.71C>T
NM_001276695.2:c.71C>T
NM_001276696.2:c.71C>T
NM_001276760.2:c.71C>T
NM_001276761.2:c.71C>T
NM_000546.6:c.188C>T
NM_001126112.3:c.188C>T
NM_001126113.3:c.188C>T
NM_001126114.3:c.188C>T
NM_001126118.2:c.71C>T
NM_001276695.3:c.71C>T
NM_001276696.3:c.71C>T
NM_001276760.3:c.71C>T
NM_001276761.3:c.71C>T
More

Benign

Met criteria codes 3
BS3 BP4 BS2_Supporting
Not Met criteria codes 13
BA1 PM2 PM1 PM5 BS4 BS1 PS2 PS4 PS3 PS1 PP4 PP1 PP3

Evidence Links 2

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.188C>T variant in TP53 is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 63 (p.Ala63Val). 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 contributor: Invitae). 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 = -0.099; 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_Supporting, BS3, BP4_Moderate. (Bayesian Points: -7; VCEP specifications version 2.1; 1/16/2025).
Met criteria codes
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).
Functional at 83% PubMed:12826609
No LOF PubMed:30224644
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.099; 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).
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 contributor: Invitae).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
The highest population minor allele frequency in gnomAD v4.1.0 is 0.00004456 (2/44880 alleles) in the East Asian population (PM2, BS1, and BA1 are 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).
PM5
2 different missense variants (p.Ala63Gly, p.Ala63Thr) in the same codon have been reported (ClinVar Variation IDs: 229693, 231015). 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).
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
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
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
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.