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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000546.5(TP53):c.1031T>C (p.Leu344Pro)

CA000021

12375 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7b4332f9-03a6-43f1-afde-508d91bd92d5

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.1031T>C

NM_000546.5(TP53):c.1031T>C (p.Leu344Pro)

NC_000017.11:g.7670678A>G

CM000679.2:g.7670678A>G

NC_000017.10:g.7573996A>G

CM000679.1:g.7573996A>G

NC_000017.9:g.7514721A>G

NG_017013.2:g.21873T>C

ENST00000503591.2:c.1031T>C

ENST00000508793.6:c.1031T>C

ENST00000509690.6:c.635T>C

ENST00000514944.6:c.752T>C

ENST00000604348.6:c.1010T>C

ENST00000269305.9:c.1031T>C

ENST00000269305.8:c.1031T>C

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

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

ENST00000420246.6:c.*138T>C

ENST00000445888.6:c.1031T>C

ENST00000455263.6:c.*50T>C

ENST00000504290.5:c.*50T>C

ENST00000504937.5:c.635T>C

ENST00000510385.5:c.*138T>C

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

ENST00000610292.4:c.914T>C

ENST00000610538.4:c.*50T>C

ENST00000610623.4:c.*50T>C

ENST00000615910.4:c.998T>C

ENST00000617185.4:c.*138T>C

ENST00000618944.4:c.*138T>C

ENST00000619186.4:c.554T>C

ENST00000619485.4:c.914T>C

ENST00000620739.4:c.914T>C

ENST00000622645.4:c.*138T>C

ENST00000635293.1:c.914T>C

NM_001126112.2:c.1031T>C

NM_001126113.2:c.*50T>C

NM_001126114.2:c.*138T>C

NM_001126115.1:c.635T>C

NM_001126116.1:c.*138T>C

NM_001126117.1:c.*50T>C

NM_001126118.1:c.914T>C

NM_001276695.1:c.*50T>C

NM_001276696.1:c.*138T>C

NM_001276697.1:c.554T>C

NM_001276698.1:c.*138T>C

NM_001276699.1:c.*50T>C

NM_001276760.1:c.914T>C

NM_001276761.1:c.914T>C

NM_001276695.2:c.*50T>C

NM_001276696.2:c.*138T>C

NM_001276697.2:c.554T>C

NM_001276698.2:c.*138T>C

NM_001276699.2:c.*50T>C

NM_001276760.2:c.914T>C

NM_001276761.2:c.914T>C

NM_000546.6:c.1031T>C

NM_001126112.3:c.1031T>C

NM_001126113.3:c.*50T>C

NM_001126114.3:c.*138T>C

NM_001126115.2:c.635T>C

NM_001126116.2:c.*138T>C

NM_001126117.2:c.*50T>C

NM_001126118.2:c.914T>C

NM_001276695.3:c.*50T>C

NM_001276696.3:c.*138T>C

NM_001276697.3:c.554T>C

NM_001276698.3:c.*138T>C

NM_001276699.3:c.*50T>C

NM_001276760.3:c.914T>C

NM_001276761.3:c.914T>C

Likely Pathogenic

PS3 PM2_Supporting PS4_Supporting PP3_Moderate

PS2 PS1 PVS1 PP4 PP1 PM1 PM4 PM5 BA1 BS2 BS4 BS3 BS1 BP3 BP4 BP7

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.1031T>C variant in TP53 is a missense variant predicted to cause substitution of leucine by proline at amino acid 344 (p.Leu344Pro). This variant has been reported in 1 proband meeting Classic criteria, and 1 proband meeting revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting PMID: 8649785, 20522432). This variant has an allele frequency of 6.195e-7 (1/1614076 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.4856; 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). In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024).

PS3

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

PM2_Supporting

This variant has an allele frequency of 6.195e-7 (1/1614076 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).

PS4_Supporting

This variant has been reported in 1 proband meeting Classic criteria, and 1 proband meeting revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 8649785, 20522432).

PP3_Moderate

Computational predictor scores (BayesDel = 0.4856; 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).

PS2