Variant: NM_000546.5(TP53):c.869G>A (p.Arg290His)

CA000468

127825 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: de5ede53-7b6d-40ad-8a0e-0b3aa4c7ecd8

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.869G>A
NM_000546.5(TP53):c.869G>A (p.Arg290His)
NC_000017.11:g.7673751C>T
CM000679.2:g.7673751C>T
NC_000017.10:g.7577069C>T
CM000679.1:g.7577069C>T
NC_000017.9:g.7517794C>T
NG_017013.2:g.18800G>A
ENST00000503591.2:c.869G>A
ENST00000508793.6:c.869G>A
ENST00000509690.6:c.473G>A
ENST00000514944.6:c.590G>A
ENST00000604348.6:c.848G>A
ENST00000269305.9:c.869G>A
ENST00000269305.8:c.869G>A
ENST00000359597.8:c.869G>A
ENST00000413465.6:c.782+430G>A
ENST00000420246.6:c.869G>A
ENST00000445888.6:c.869G>A
ENST00000455263.6:c.869G>A
ENST00000504290.5:c.473G>A
ENST00000504937.5:c.473G>A
ENST00000509690.5:c.473G>A
ENST00000510385.5:c.473G>A
ENST00000610292.4:c.752G>A
ENST00000610538.4:c.752G>A
ENST00000610623.4:c.392G>A
ENST00000615910.4:c.836G>A
ENST00000617185.4:c.869G>A
ENST00000618944.4:c.392G>A
ENST00000619186.4:c.392G>A
ENST00000619485.4:c.752G>A
ENST00000620739.4:c.752G>A
ENST00000622645.4:c.752G>A
ENST00000635293.1:c.752G>A
NM_001126112.2:c.869G>A
NM_001126113.2:c.869G>A
NM_001126114.2:c.869G>A
NM_001126115.1:c.473G>A
NM_001126116.1:c.473G>A
NM_001126117.1:c.473G>A
NM_001126118.1:c.752G>A
NM_001276695.1:c.752G>A
NM_001276696.1:c.752G>A
NM_001276697.1:c.392G>A
NM_001276698.1:c.392G>A
NM_001276699.1:c.392G>A
NM_001276760.1:c.752G>A
NM_001276761.1:c.752G>A
NM_001276695.2:c.752G>A
NM_001276696.2:c.752G>A
NM_001276697.2:c.392G>A
NM_001276698.2:c.392G>A
NM_001276699.2:c.392G>A
NM_001276760.2:c.752G>A
NM_001276761.2:c.752G>A
NM_000546.6:c.869G>A
NM_001126112.3:c.869G>A
NM_001126113.3:c.869G>A
NM_001126114.3:c.869G>A
NM_001126115.2:c.473G>A
NM_001126116.2:c.473G>A
NM_001126117.2:c.473G>A
NM_001126118.2:c.752G>A
NM_001276695.3:c.752G>A
NM_001276696.3:c.752G>A
NM_001276697.3:c.392G>A
NM_001276698.3:c.392G>A
NM_001276699.3:c.392G>A
NM_001276760.3:c.752G>A
NM_001276761.3:c.752G>A

Benign

• Met criteria codes: BS2 BS3 BP4

• Not Met criteria codes: BS4 BS1 BP3 BP2 BP7 BP5 PM1 PM5 PM4 PM3 PS1 PS4 PS2 PS3 BA1 PM2 PVS1 PP1 PP3 PP4

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.869G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 290 (p.Arg290His). 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; SCV000187277.8). 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 = 0.09; Align GVGD Class 0) 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 Benign for Li Fraumeni Syndrome. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, BP4 (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; SCV000187277.8).
• 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 = 0.09; Align GVGD Class 0) 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).

Not Met criteria codes

• 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
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: 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 (p.Arg290Leu; p.Arg290Pro; p.Arg290Gly; p.Arg290Cys) in the same codon have been reported (ClinVar Variation IDs: 633445, 458572, 628970, 216472). However, the 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).
• PM4: 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
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant has been observed in 2 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs: 10435620, 19468865) but this evidence is not applied as PM2_Supporting is not applied.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: IARC database calls this supertrans & 2 studies show no effect on protein.
• 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 v41.0 is 0.0002602 (307/1180030 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
• PVS1: 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
• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline