Variant: NM_000546.5(TP53):c.892G>A (p.Glu298Lys)

CA000483

141483 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 8fb68094-5560-49d6-a48b-2a63d4e67265

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.892G>A
NM_000546.5(TP53):c.892G>A (p.Glu298Lys)
NC_000017.11:g.7673728C>T
CM000679.2:g.7673728C>T
NC_000017.10:g.7577046C>T
CM000679.1:g.7577046C>T
NC_000017.9:g.7517771C>T
NG_017013.2:g.18823G>A
ENST00000503591.2:c.892G>A
ENST00000508793.6:c.892G>A
ENST00000509690.6:c.496G>A
ENST00000514944.6:c.613G>A
ENST00000604348.6:c.871G>A
ENST00000269305.9:c.892G>A
ENST00000269305.8:c.892G>A
ENST00000359597.8:c.892G>A
ENST00000413465.6:c.782+453G>A
ENST00000420246.6:c.892G>A
ENST00000445888.6:c.892G>A
ENST00000455263.6:c.892G>A
ENST00000504290.5:c.496G>A
ENST00000504937.5:c.496G>A
ENST00000509690.5:c.496G>A
ENST00000510385.5:c.496G>A
ENST00000610292.4:c.775G>A
ENST00000610538.4:c.775G>A
ENST00000610623.4:c.415G>A
ENST00000615910.4:c.859G>A
ENST00000617185.4:c.892G>A
ENST00000618944.4:c.415G>A
ENST00000619186.4:c.415G>A
ENST00000619485.4:c.775G>A
ENST00000620739.4:c.775G>A
ENST00000622645.4:c.775G>A
ENST00000635293.1:c.775G>A
NM_001126112.2:c.892G>A
NM_001126113.2:c.892G>A
NM_001126114.2:c.892G>A
NM_001126115.1:c.496G>A
NM_001126116.1:c.496G>A
NM_001126117.1:c.496G>A
NM_001126118.1:c.775G>A
NM_001276695.1:c.775G>A
NM_001276696.1:c.775G>A
NM_001276697.1:c.415G>A
NM_001276698.1:c.415G>A
NM_001276699.1:c.415G>A
NM_001276760.1:c.775G>A
NM_001276761.1:c.775G>A
NM_001276695.2:c.775G>A
NM_001276696.2:c.775G>A
NM_001276697.2:c.415G>A
NM_001276698.2:c.415G>A
NM_001276699.2:c.415G>A
NM_001276760.2:c.775G>A
NM_001276761.2:c.775G>A
NM_000546.6:c.892G>A
NM_001126112.3:c.892G>A
NM_001126113.3:c.892G>A
NM_001126114.3:c.892G>A
NM_001126115.2:c.496G>A
NM_001126116.2:c.496G>A
NM_001126117.2:c.496G>A
NM_001126118.2:c.775G>A
NM_001276695.3:c.775G>A
NM_001276696.3:c.775G>A
NM_001276697.3:c.415G>A
NM_001276698.3:c.415G>A
NM_001276699.3:c.415G>A
NM_001276760.3:c.775G>A
NM_001276761.3:c.775G>A

Benign

• Met criteria codes: BS3 BS2 BP4

• Not Met criteria codes: PS2 PS4 PS1 PS3 BA1 PP4 PP1 PP2 PP3 PM1 PM4 PM5 PM2 BS4 BS1 BP7 BP3 BP1 PVS1

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.892G>A variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 298 (p.Gly298Lys). This variant has been observed in 4-7 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_Moderate; SCV000184859, SCV000260657). 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 = -0.199; 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). 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_Moderate, BS3, BP4_Moderate. (Bayesian Points: -8; VCEP specifications version 2.0; 7/24/2024)

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).
• BS2: BS2_MODERATE APPLIED This variant has been observed in 4-7 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_Moderate; SCV000184859, SCV000260657).
• BP4: BP4_MODERATE APPLIED Computational predictor scores (BayesDel = -0.198; 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

• 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
• BA1: 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
• PP2: 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: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: 2 different missense variants (c.893A>G, p.Glu298Gly and c.892G>C, p.Glu298Gln) in the same codon have been reported (ClinVar Variation ID: 927512, 1495821). 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).
• PM2: The highest population minor allele frequency in gnomAD v41.0 is 0.00008332 (5/60008 alleles) in the Admixed American population (PM2, BS1, and BA1 are 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
• BP7: 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
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline