Variant: NM_001276761.1:c.-21-1G>A

CA397848094

638853 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: b8bc495e-5c4e-42b1-89c3-4e8dbb41b60b

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_001276761.1:c.-21-1G>A
NC_000017.11:g.7676273C>T
CM000679.2:g.7676273C>T
NC_000017.10:g.7579591C>T
CM000679.1:g.7579591C>T
NC_000017.9:g.7520316C>T
NG_017013.2:g.16278G>A
ENST00000503591.2:c.97-1G>A
ENST00000508793.6:c.97-1G>A
ENST00000509690.6:c.-21-1037G>A
ENST00000514944.6:c.96+109G>A
ENST00000604348.6:c.97-1G>A
ENST00000269305.9:c.97-1G>A
ENST00000269305.8:c.97-1G>A
ENST00000359597.8:c.97-1G>A
ENST00000413465.6:c.97-1G>A
ENST00000420246.6:c.97-1G>A
ENST00000445888.6:c.97-1G>A
ENST00000455263.6:c.97-1G>A
ENST00000503591.1:c.97-1G>A
ENST00000505014.5:n.353-1G>A
ENST00000508793.5:c.97-1G>A
ENST00000509690.5:c.-21-1037G>A
ENST00000514944.5:c.96+109G>A
ENST00000604348.5:c.97-1G>A
ENST00000610292.4:c.-21-1G>A
ENST00000610538.4:c.-21-1G>A
ENST00000615910.4:c.97-1G>A
ENST00000617185.4:c.97-1G>A
ENST00000619485.4:c.-21-1G>A
ENST00000620739.4:c.-21-1G>A
ENST00000622645.4:c.-21-1G>A
ENST00000635293.1:c.-21-1G>A
NM_000546.5:c.97-1G>A
NM_001126112.2:c.97-1G>A
NM_001126113.2:c.97-1G>A
NM_001126114.2:c.97-1G>A
NM_001126118.1:c.-21-1G>A
NM_001276695.1:c.-21-1G>A
NM_001276696.1:c.-21-1G>A
NM_001276760.1:c.-21-1G>A
NM_001276695.2:c.-21-1G>A
NM_001276696.2:c.-21-1G>A
NM_001276760.2:c.-21-1G>A
NM_001276761.2:c.-21-1G>A
NM_000546.6:c.97-1G>A
NM_001126112.3:c.97-1G>A
NM_001126113.3:c.97-1G>A
NM_001126114.3:c.97-1G>A
NM_001126118.2:c.-21-1G>A
NM_001276695.3:c.-21-1G>A
NM_001276696.3:c.-21-1G>A
NM_001276760.3:c.-21-1G>A
NM_001276761.3:c.-21-1G>A

Pathogenic

• Met criteria codes: PP4_Moderate PM2_Supporting PVS1 PS4_Supporting

• Not Met criteria codes: BA1 BS2 BS4 BS3 BS1 BP4 PS1 PS3 PS2 PP1 PP3 PM1 PM5

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.97-1G>A is a TP53 variant within the canonical acceptor site of exon 4. (PVS1 (RNA); PMIDs :9792154, 11420676). This variant has been reported in 1 proband meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID 9242456, Internal lab contributors: SCV001181068.4). At least one individual with this variant was found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, Internal lab contributors: SCV001181068.4). This variant is absent from gnomAD v4.1.0 (PM2_Supporting).. In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PVS1, PS4_Supporting, PP4_moderate, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 7/24/2024)

Met criteria codes

• PP4_Moderate: At least one individual with this variant was found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, Internal lab contributors: SCV001181068.4).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PVS1: PVS1 (RNA):The NM_000546.6 c.97-1G>A is a TP53 variant within the canonical acceptor site of exon 4. (PVS1 (RNA); PMIDs :9792154, 11420676).
• PS4_Supporting: This variant has been reported in 1 proband meeting Revised Chompret criteria and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID 9242456, Internal lab contributors: SCV001181068.4).

Not Met criteria codes

• BA1: 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
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: 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
• BP4: 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: PVS1_Strength (RNA) to be used to designate capture of splicing data (not PS3)
• PS2: 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: The computational splicing predictor SpliceAI gives a score of 0.99, predicting that the variant has an impact on splicing (score threshold > 0.20). PP3 should not be used in combination with PVS1
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline