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.760A>G (p.Ile254Val)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA001720

406605 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fca61001-1f1b-4755-907b-f96fc6002915

Approved on: 2025-01-16

Published on: 2025-01-16

HGVS expressions

NM_000546.6:c.760A>G

NM_000546.6(TP53):c.760A>G (p.Ile254Val)

NC_000017.11:g.7674203T>C

CM000679.2:g.7674203T>C

NC_000017.10:g.7577521T>C

CM000679.1:g.7577521T>C

NC_000017.9:g.7518246T>C

NG_017013.2:g.18348A>G

ENST00000503591.2:c.760A>G

ENST00000508793.6:c.760A>G

ENST00000509690.6:c.364A>G

ENST00000514944.6:c.481A>G

ENST00000604348.6:c.739A>G

ENST00000269305.9:c.760A>G

ENST00000269305.8:c.760A>G

ENST00000359597.8:c.760A>G

ENST00000413465.6:c.760A>G

ENST00000420246.6:c.760A>G

ENST00000445888.6:c.760A>G

ENST00000455263.6:c.760A>G

ENST00000504290.5:c.364A>G

ENST00000504937.5:c.364A>G

ENST00000509690.5:c.364A>G

ENST00000510385.5:c.364A>G

ENST00000610292.4:c.643A>G

ENST00000610538.4:c.643A>G

ENST00000610623.4:c.283A>G

ENST00000615910.4:c.727A>G

ENST00000617185.4:c.760A>G

ENST00000618944.4:c.283A>G

ENST00000619186.4:c.283A>G

ENST00000619485.4:c.643A>G

ENST00000620739.4:c.643A>G

ENST00000622645.4:c.643A>G

ENST00000635293.1:c.643A>G

NM_000546.5:c.760A>G

NM_001126112.2:c.760A>G

NM_001126113.2:c.760A>G

NM_001126114.2:c.760A>G

NM_001126115.1:c.364A>G

NM_001126116.1:c.364A>G

NM_001126117.1:c.364A>G

NM_001126118.1:c.643A>G

NM_001276695.1:c.643A>G

NM_001276696.1:c.643A>G

NM_001276697.1:c.283A>G

NM_001276698.1:c.283A>G

NM_001276699.1:c.283A>G

NM_001276760.1:c.643A>G

NM_001276761.1:c.643A>G

NM_001276695.2:c.643A>G

NM_001276696.2:c.643A>G

NM_001276697.2:c.283A>G

NM_001276698.2:c.283A>G

NM_001276699.2:c.283A>G

NM_001276760.2:c.643A>G

NM_001276761.2:c.643A>G

NM_001126112.3:c.760A>G

NM_001126113.3:c.760A>G

NM_001126114.3:c.760A>G

NM_001126115.2:c.364A>G

NM_001126116.2:c.364A>G

NM_001126117.2:c.364A>G

NM_001126118.2:c.643A>G

NM_001276695.3:c.643A>G

NM_001276696.3:c.643A>G

NM_001276697.3:c.283A>G

NM_001276698.3:c.283A>G

NM_001276699.3:c.283A>G

NM_001276760.3:c.643A>G

NM_001276761.3:c.643A>G

Likely Benign

PM2_Supporting BS2 BS3 PM1_Supporting PP3

BA1 PM6 PM5 BS4 BS1 BP2 BP4 PS2 PS4 PS3 PS1 PP1

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 2.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6:c.760A>G variant in TP53 is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 254 (p.Ile254Val). This variant has been observed in 4-7 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_Moderate; Internal lab contributor: ClinVar SCV000545356.10). This variant has an allele frequency of 0.000006821 (11/1612700 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.1708; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). 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_Moderate, PM2_Supporting, BS3, PP3, PM1_Supporting. (Bayesian Points: -3; VCEP specifications version 2.2; 1/16/2025).

PM2_Supporting

This variant has an allele frequency of 0.000006821 (11/1612700 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).

BS2

BS2_MODERATE. This variant has been observed in 4-7 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_Moderate; Internal lab contributor: ClinVar SCV000545356.10).

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).

PM1_Supporting

This variant has 2 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).

PP3

Computational predictor scores (BayesDel = 0.1708; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3).

BA1