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_000546.6(TP53):c.1015G>C (p.Glu339Gln)

CA000018

141893 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 45b695a1-6c52-483f-96cd-093976098264

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000546.6:c.1015G>C

NM_000546.6(TP53):c.1015G>C (p.Glu339Gln)

NC_000017.11:g.7670694C>G

CM000679.2:g.7670694C>G

NC_000017.10:g.7574012C>G

CM000679.1:g.7574012C>G

NC_000017.9:g.7514737C>G

NG_017013.2:g.21857G>C

ENST00000503591.2:c.1015G>C

ENST00000508793.6:c.1015G>C

ENST00000509690.6:c.619G>C

ENST00000514944.6:c.736G>C

ENST00000604348.6:c.994G>C

ENST00000269305.9:c.1015G>C

ENST00000269305.8:c.1015G>C

ENST00000359597.8:c.993+2841G>C

ENST00000413465.6:c.782+3487G>C

ENST00000420246.6:c.*122G>C

ENST00000445888.6:c.1015G>C

ENST00000455263.6:c.*34G>C

ENST00000504290.5:c.*34G>C

ENST00000504937.5:c.619G>C

ENST00000510385.5:c.*122G>C

ENST00000576024.1:c.54-1004G>C

ENST00000610292.4:c.898G>C

ENST00000610538.4:c.*34G>C

ENST00000610623.4:c.*34G>C

ENST00000615910.4:c.982G>C

ENST00000617185.4:c.*122G>C

ENST00000618944.4:c.*122G>C

ENST00000619186.4:c.538G>C

ENST00000619485.4:c.898G>C

ENST00000620739.4:c.898G>C

ENST00000622645.4:c.*122G>C

ENST00000635293.1:c.898G>C

NM_000546.5:c.1015G>C

NM_001126112.2:c.1015G>C

NM_001126113.2:c.*34G>C

NM_001126114.2:c.*122G>C

NM_001126115.1:c.619G>C

NM_001126116.1:c.*122G>C

NM_001126117.1:c.*34G>C

NM_001126118.1:c.898G>C

NM_001276695.1:c.*34G>C

NM_001276696.1:c.*122G>C

NM_001276697.1:c.538G>C

NM_001276698.1:c.*122G>C

NM_001276699.1:c.*34G>C

NM_001276760.1:c.898G>C

NM_001276761.1:c.898G>C

NM_001276695.2:c.*34G>C

NM_001276696.2:c.*122G>C

NM_001276697.2:c.538G>C

NM_001276698.2:c.*122G>C

NM_001276699.2:c.*34G>C

NM_001276760.2:c.898G>C

NM_001276761.2:c.898G>C

NM_001126112.3:c.1015G>C

NM_001126113.3:c.*34G>C

NM_001126114.3:c.*122G>C

NM_001126115.2:c.619G>C

NM_001126116.2:c.*122G>C

NM_001126117.2:c.*34G>C

NM_001126118.2:c.898G>C

NM_001276695.3:c.*34G>C

NM_001276696.3:c.*122G>C

NM_001276697.3:c.538G>C

NM_001276698.3:c.*122G>C

NM_001276699.3:c.*34G>C

NM_001276760.3:c.898G>C

NM_001276761.3:c.898G>C

Likely Benign

BS3 BP4 PS4_Supporting BS2_Supporting

BS4 BS1 BA1 PS2 PS3 PS1 PP4 PP1 PP3 PM1 PM2

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.1015G>C variant in TP53 is a missense variant predicted to cause substitution of glutamic acid by glutamine at amino acid 339 (p.Glu339Gln). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been observed in 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry lab). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, this variant meets the criteria to be classified as likely benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_supporting, BS3, BP4. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024).

BS3

In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).

BP4

Computational predictor scores (BayesDel = 0.0408311; Align GVGD Class C0) are below the recommended thresholds (BayesDel < 0.16 and > -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).

PS4_Supporting

This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. 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: 28573494; Internal lab contributor: Laboratoire de Génétique Moléculaire du CHU de Rouen). This code is not applied as variant does not meet PM2_Supporting

BS2_Supporting

This variant has been observed in 2 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; Ambry lab).

BS4