Variant: NM_001126112.2(TP53):c.250G>A (p.Ala84Thr)

CA000085

140833 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 37964f4e-7d50-4830-ba30-a640ab3afdb2

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_001126112.2:c.250G>A
NM_001126112.2(TP53):c.250G>A (p.Ala84Thr)
NC_000017.11:g.7676119C>T
CM000679.2:g.7676119C>T
NC_000017.10:g.7579437C>T
CM000679.1:g.7579437C>T
NC_000017.9:g.7520162C>T
NG_017013.2:g.16432G>A
ENST00000503591.2:c.250G>A
ENST00000508793.6:c.250G>A
ENST00000509690.6:c.-21-883G>A
ENST00000514944.6:c.96+263G>A
ENST00000604348.6:c.250G>A
ENST00000269305.9:c.250G>A
ENST00000269305.8:c.250G>A
ENST00000359597.8:c.250G>A
ENST00000413465.6:c.250G>A
ENST00000420246.6:c.250G>A
ENST00000445888.6:c.250G>A
ENST00000455263.6:c.250G>A
ENST00000503591.1:c.250G>A
ENST00000505014.5:n.506G>A
ENST00000508793.5:c.250G>A
ENST00000509690.5:c.-21-883G>A
ENST00000514944.5:c.96+263G>A
ENST00000604348.5:c.250G>A
ENST00000610292.4:c.133G>A
ENST00000610538.4:c.133G>A
ENST00000615910.4:c.250G>A
ENST00000617185.4:c.250G>A
ENST00000619485.4:c.133G>A
ENST00000620739.4:c.133G>A
ENST00000622645.4:c.133G>A
ENST00000635293.1:c.133G>A
NM_000546.5:c.250G>A
NM_001126113.2:c.250G>A
NM_001126114.2:c.250G>A
NM_001126118.1:c.133G>A
NM_001276695.1:c.133G>A
NM_001276696.1:c.133G>A
NM_001276760.1:c.133G>A
NM_001276761.1:c.133G>A
NM_001276695.2:c.133G>A
NM_001276696.2:c.133G>A
NM_001276760.2:c.133G>A
NM_001276761.2:c.133G>A
NM_000546.6:c.250G>A
NM_001126112.3:c.250G>A
NM_001126113.3:c.250G>A
NM_001126114.3:c.250G>A
NM_001126118.2:c.133G>A
NM_001276695.3:c.133G>A
NM_001276696.3:c.133G>A
NM_001276760.3:c.133G>A
NM_001276761.3:c.133G>A

Likely Benign

• Met criteria codes: BS3 BP4

• Not Met criteria codes: BA1 BS4 BS1 BS2 PS2 PS4 PS3 PS1 PP4 PP1 PP3 PM1 PM5 PM2

Expert Panel

TP53 VCEP

Criteria Specification Information

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

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.250G>A variant in TP53 is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 84 (p.Ala84Thr). 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 = -0.0501; 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 for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BP4_Moderate, BS3. (Bayesian Points: -6; 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).
• BP4: BP4_MODERATE Computational predictor scores (BayesDel = -0.0501; 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).

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
• BS2: 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
• 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.251C>T, p.Ala84Val) in the same codon has been reported (ClinVar Variation ID: 1792511). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
• PM2: The highest population minor allele frequency in gnomAD v4.1.0 is 0.00008341 (5/59944 alleles) in the Admixed American population (PM2, BS1, and BA1 are not met).