Variant: NM_000546.6(TP53):c.1039G>A (p.Ala347Thr)

CA397832443

662690 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 7f173dab-a4a2-4eb3-a26e-9fa566be43e1

Approved on: 2025-05-07

Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.1039G>A
NM_000546.6(TP53):c.1039G>A (p.Ala347Thr)
NC_000017.11:g.7670670C>T
CM000679.2:g.7670670C>T
NC_000017.10:g.7573988C>T
CM000679.1:g.7573988C>T
NC_000017.9:g.7514713C>T
NG_017013.2:g.21881G>A
ENST00000503591.2:c.1039G>A
ENST00000508793.6:c.1039G>A
ENST00000509690.6:c.643G>A
ENST00000514944.6:c.760G>A
ENST00000604348.6:c.1018G>A
ENST00000269305.9:c.1039G>A
ENST00000269305.8:c.1039G>A
ENST00000359597.8:c.993+2865G>A
ENST00000413465.6:c.782+3511G>A
ENST00000420246.6:c.*146G>A
ENST00000445888.6:c.1039G>A
ENST00000455263.6:c.*58G>A
ENST00000504290.5:c.*58G>A
ENST00000504937.5:c.643G>A
ENST00000510385.5:c.*146G>A
ENST00000576024.1:c.54-980G>A
ENST00000610292.4:c.922G>A
ENST00000610538.4:c.*58G>A
ENST00000610623.4:c.*58G>A
ENST00000615910.4:c.1006G>A
ENST00000617185.4:c.*146G>A
ENST00000618944.4:c.*146G>A
ENST00000619186.4:c.562G>A
ENST00000619485.4:c.922G>A
ENST00000620739.4:c.922G>A
ENST00000622645.4:c.*146G>A
ENST00000635293.1:c.922G>A
NM_000546.5:c.1039G>A
NM_001126112.2:c.1039G>A
NM_001126113.2:c.*58G>A
NM_001126114.2:c.*146G>A
NM_001126115.1:c.643G>A
NM_001126116.1:c.*146G>A
NM_001126117.1:c.*58G>A
NM_001126118.1:c.922G>A
NM_001276695.1:c.*58G>A
NM_001276696.1:c.*146G>A
NM_001276697.1:c.562G>A
NM_001276698.1:c.*146G>A
NM_001276699.1:c.*58G>A
NM_001276760.1:c.922G>A
NM_001276761.1:c.922G>A
NM_001276695.2:c.*58G>A
NM_001276696.2:c.*146G>A
NM_001276697.2:c.562G>A
NM_001276698.2:c.*146G>A
NM_001276699.2:c.*58G>A
NM_001276760.2:c.922G>A
NM_001276761.2:c.922G>A
NM_001126112.3:c.1039G>A
NM_001126113.3:c.*58G>A
NM_001126114.3:c.*146G>A
NM_001126115.2:c.643G>A
NM_001126116.2:c.*146G>A
NM_001126117.2:c.*58G>A
NM_001126118.2:c.922G>A
NM_001276695.3:c.*58G>A
NM_001276696.3:c.*146G>A
NM_001276697.3:c.562G>A
NM_001276698.3:c.*146G>A
NM_001276699.3:c.*58G>A
NM_001276760.3:c.922G>A
NM_001276761.3:c.922G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting BP4 PS4 PP4 PP1

• Not Met criteria codes: BS4 BS3 BS1 PS3 PS1 PS2 BA1 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 2.3.0

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.1039G>A variant in TP53 is a missense variant predicted to cause substitution of alanine by threonine at amino acid 347 (p.Ala347Thr). This variant has been reported in 2 families meeting Classic LFS criteria and 6 unrelated probands meeting Revised Chompret criteria. In addition, this variant was identified in 1 female with HER2+ breast cancer under the age of 40. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 37437600; 33249490, 34906214, Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 3 families (PP1; Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). Based on this evidence, this variant scores 4.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 37437600; 33249490, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644). Computational predictor scores (BayesDel = -0.0187547; 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). 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). In summary, this variant is classified as a variant of unknown significance for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4, PP1, PP4, BP4_Moderate, PM2_Supporting. (Bayesian Points: 5; VCEP specifications version 2.3)

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• BP4: BP4_MODERATE Computational predictor scores (BayesDel = -0.0187547; 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).
• PS4: This variant has been reported in 2 families meeting Classic LFS criteria and 6 unrelated probands meeting Revised Chompret criteria. In addition, this variant was identified in 1 female with HER2+ breast cancer under the age of 40. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 37437600; 33249490, 34906214, Internal lab contributors).
• PP4: At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors).
• PP1: The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 3 families (PP1; Internal lab contributors).

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3_Supporting not met; PMIDs: 12826609, 30224644).
• BS1: 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
• PS2: 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
• 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: 1 other missense variant (c.1040C>A, p.Ala347Asp) in the same codon has been reported (ClinVar Variation IDs: 43587). However, this variant does not meet criteria for PM5 code application (PM5 not met).