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

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

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

ENST00000269305.8:c.1031T>C

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

ENST00000413465.6:n.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:n.54-988T>C

ENST00000610292.4:c.914T>C

ENST00000610538.4:c.*50T>C

ENST00000610623.4:c.*50T>C

ENST00000615910.4:n.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

Likely Pathogenic

PM2_Supporting PS3 PS4_Moderate PP3_Moderate

Evidence Links 3

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). Additionally, transactivation assays show a low functioning allele according to Kato, et al. and there is a tetramerization assay demonstrating a mutant protein that only forms dimers (PS3; PMID: 12826609, PMID: 9704930). This variant has been reported in 2 probands meeting Classic LI-FRAUMENI SYNDROMEcriteria (PS4_Moderate; PMID: 8649785, 20522432). In summary, TP53 c.1031T>C; p.Leu344Pro meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PS3, PS4_Moderate.

PM2_Supporting

Absent in population databases

PS3

T-A assays suggest non-functional allele; other studies show loss of growth suppression in colon formation & abnl tetramer formation

Abnl tetramer formation PubMed:9704930

PS4_Moderate

2 probands meeting LFS = 2 pts

1 proband meeting LFS criteria PubMed:8649785

1 proband meeting LFS criteria PubMed:20522432

PP3_Moderate

AGVGD = Class C65 & BayesDel score >0.16

Approved on: 2019-08-28

Published on: 2020-01-24

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