Variant: NM_000546.5(TP53):c.875A>G (p.Lys292Arg)

CA16615993

406577 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 7ecc92d2-f4ef-4396-b065-463440589f86

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_000546.5:c.875A>G
NM_000546.5(TP53):c.875A>G (p.Lys292Arg)
NC_000017.11:g.7673745T>C
CM000679.2:g.7673745T>C
NC_000017.10:g.7577063T>C
CM000679.1:g.7577063T>C
NC_000017.9:g.7517788T>C
NG_017013.2:g.18806A>G
ENST00000503591.2:c.875A>G
ENST00000508793.6:c.875A>G
ENST00000509690.6:c.479A>G
ENST00000514944.6:c.596A>G
ENST00000604348.6:c.854A>G
ENST00000269305.9:c.875A>G
ENST00000269305.8:c.875A>G
ENST00000359597.8:c.875A>G
ENST00000413465.6:c.782+436A>G
ENST00000420246.6:c.875A>G
ENST00000445888.6:c.875A>G
ENST00000455263.6:c.875A>G
ENST00000504290.5:c.479A>G
ENST00000504937.5:c.479A>G
ENST00000509690.5:c.479A>G
ENST00000510385.5:c.479A>G
ENST00000610292.4:c.758A>G
ENST00000610538.4:c.758A>G
ENST00000610623.4:c.398A>G
ENST00000615910.4:c.842A>G
ENST00000617185.4:c.875A>G
ENST00000618944.4:c.398A>G
ENST00000619186.4:c.398A>G
ENST00000619485.4:c.758A>G
ENST00000620739.4:c.758A>G
ENST00000622645.4:c.758A>G
ENST00000635293.1:c.758A>G
NM_001126112.2:c.875A>G
NM_001126113.2:c.875A>G
NM_001126114.2:c.875A>G
NM_001126115.1:c.479A>G
NM_001126116.1:c.479A>G
NM_001126117.1:c.479A>G
NM_001126118.1:c.758A>G
NM_001276695.1:c.758A>G
NM_001276696.1:c.758A>G
NM_001276697.1:c.398A>G
NM_001276698.1:c.398A>G
NM_001276699.1:c.398A>G
NM_001276760.1:c.758A>G
NM_001276761.1:c.758A>G
NM_001276695.2:c.758A>G
NM_001276696.2:c.758A>G
NM_001276697.2:c.398A>G
NM_001276698.2:c.398A>G
NM_001276699.2:c.398A>G
NM_001276760.2:c.758A>G
NM_001276761.2:c.758A>G
NM_000546.6:c.875A>G
NM_001126112.3:c.875A>G
NM_001126113.3:c.875A>G
NM_001126114.3:c.875A>G
NM_001126115.2:c.479A>G
NM_001126116.2:c.479A>G
NM_001126117.2:c.479A>G
NM_001126118.2:c.758A>G
NM_001276695.3:c.758A>G
NM_001276696.3:c.758A>G
NM_001276697.3:c.398A>G
NM_001276698.3:c.398A>G
NM_001276699.3:c.398A>G
NM_001276760.3:c.758A>G
NM_001276761.3:c.758A>G

Likely Benign

• Met criteria codes: BS3 BP4 PM2_Supporting

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

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.875A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 292 (p.Lys292Arg). This variant has an allele frequency of 6.196e-7 (1/1614016 alleles) across gnomAD v4.1.0 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 = 0.00998; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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). 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: PM2_Supporting, BS3, BP4. (Bayesian Points: -4; VCEP specifications version 2.2; 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: Computational predictor scores (BayesDel = 0.00998; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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).
• PM2_Supporting: This variant has an allele frequency of 6.196e-7 (1/1614016 alleles) across gnomAD v4.1.0 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

• BS4: 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
• 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
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 5 different missense variants in the same codon have been reported (ClinVar Variation IDs: 2679235, 1718571, 1021706, 12378, 1006477). However, these variants all have Grantham scores higher than the variant being evaluated (PM5 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).