Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000546.6(TP53):c.1031T>G (p.Leu344Arg)

CA397832502

2758378 (ClinVar)

Gene: TP53 (HGNC:7157)

Condition: Li-Fraumeni syndrome (MONDO:0018875)

Inheritance Mode: Autosomal dominant inheritance

UUID: 18d0d2fa-742f-4ec6-b0d5-5ae1682e44c4

Approved on: 2026-02-05

Published on: 2026-02-10

HGVS expressions

NM_000546.6(TP53):c.1031T>G (p.Leu344Arg)

NM_000546.6:c.1031T>G

NC_000017.11:g.7670678A>C

CM000679.2:g.7670678A>C

NC_000017.10:g.7573996A>C

CM000679.1:g.7573996A>C

NC_000017.9:g.7514721A>C

NG_017013.2:g.21873T>G

ENST00000503591.2:c.1031T>G

ENST00000508793.6:c.1031T>G

ENST00000509690.6:c.635T>G

ENST00000514944.6:c.752T>G

ENST00000604348.6:c.1010T>G

ENST00000269305.9:c.1031T>G

ENST00000269305.8:c.1031T>G

ENST00000359597.8:c.993+2857T>G

ENST00000413465.6:c.782+3503T>G

ENST00000420246.6:c.*138T>G

ENST00000445888.6:c.1031T>G

ENST00000455263.6:c.*50T>G

ENST00000504290.5:c.*50T>G

ENST00000504937.5:c.635T>G

ENST00000510385.5:c.*138T>G

ENST00000576024.1:c.54-988T>G

ENST00000610292.4:c.914T>G

ENST00000610538.4:c.*50T>G

ENST00000610623.4:c.*50T>G

ENST00000615910.4:c.998T>G

ENST00000617185.4:c.*138T>G

ENST00000618944.4:c.*138T>G

ENST00000619186.4:c.554T>G

ENST00000619485.4:c.914T>G

ENST00000620739.4:c.914T>G

ENST00000622645.4:c.*138T>G

ENST00000635293.1:c.914T>G

NM_000546.5:c.1031T>G

NM_001126112.2:c.1031T>G

NM_001126113.2:c.*50T>G

NM_001126114.2:c.*138T>G

NM_001126115.1:c.635T>G

NM_001126116.1:c.*138T>G

NM_001126117.1:c.*50T>G

NM_001126118.1:c.914T>G

NM_001276695.1:c.*50T>G

NM_001276696.1:c.*138T>G

NM_001276697.1:c.554T>G

NM_001276698.1:c.*138T>G

NM_001276699.1:c.*50T>G

NM_001276760.1:c.914T>G

NM_001276761.1:c.914T>G

NM_001276695.2:c.*50T>G

NM_001276696.2:c.*138T>G

NM_001276697.2:c.554T>G

NM_001276698.2:c.*138T>G

NM_001276699.2:c.*50T>G

NM_001276760.2:c.914T>G

NM_001276761.2:c.914T>G

NM_001126112.3:c.1031T>G

NM_001126113.3:c.*50T>G

NM_001126114.3:c.*138T>G

NM_001126115.2:c.635T>G

NM_001126116.2:c.*138T>G

NM_001126117.2:c.*50T>G

NM_001126118.2:c.914T>G

NM_001276695.3:c.*50T>G

NM_001276696.3:c.*138T>G

NM_001276697.3:c.554T>G

NM_001276698.3:c.*138T>G

NM_001276699.3:c.*50T>G

NM_001276760.3:c.914T>G

NM_001276761.3:c.914T>G

Likely Pathogenic

PP3_Moderate PS3 PM5_Supporting PM2_Supporting

BP4 BS3 BS1 PS4 PS1 BA1 PM1

Evidence Links 0

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.4.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6: c.1031T>G variant in TP53 is a missense variant predicted to cause substitution of leucine by arginine at amino acid 344 (p.Leu344Arg). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; PMID: 34196900, 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 non-functional transactivation and loss of growth suppression activity as well as impaired tetramer formation (PMIDs: 12826609, 30224644 16007150) (PS3). Computational predictor scores (BayesDel = 0.2882; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). Another missense variant (c.1031T>C, p.Leu344Pro) (ClinVar Variation ID: 12375), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, PS3, PP3_Moderate, PM5_Supporting. (Bayesian Points: 8; VCEP specifications version 2.4)

PP3_Moderate

Computational predictor scores (BayesDel = 0.2882; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).

PS3

In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity by the majority of available assays indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965, 39774325).

PM5_Supporting

Another missense variant (c.1031T>C, p.Leu344Pro) (ClinVar Variation ID: 12375), in the same codon has been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

BP4