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.1009C>G (p.Arg337Gly)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10583674

237938 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 51843582-881e-436c-b252-79aa7face271

Approved on: 2025-05-07

Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.1009C>G

NM_000546.6(TP53):c.1009C>G (p.Arg337Gly)

NC_000017.11:g.7670700G>C

CM000679.2:g.7670700G>C

NC_000017.10:g.7574018G>C

CM000679.1:g.7574018G>C

NC_000017.9:g.7514743G>C

NG_017013.2:g.21851C>G

ENST00000503591.2:c.1009C>G

ENST00000508793.6:c.1009C>G

ENST00000509690.6:c.613C>G

ENST00000514944.6:c.730C>G

ENST00000604348.6:c.988C>G

ENST00000269305.9:c.1009C>G

ENST00000269305.8:c.1009C>G

ENST00000359597.8:c.993+2835C>G

ENST00000413465.6:c.782+3481C>G

ENST00000420246.6:c.*116C>G

ENST00000445888.6:c.1009C>G

ENST00000455263.6:c.*28C>G

ENST00000504290.5:c.*28C>G

ENST00000504937.5:c.613C>G

ENST00000510385.5:c.*116C>G

ENST00000576024.1:c.54-1010C>G

ENST00000610292.4:c.892C>G

ENST00000610538.4:c.*28C>G

ENST00000610623.4:c.*28C>G

ENST00000615910.4:c.976C>G

ENST00000617185.4:c.*116C>G

ENST00000618944.4:c.*116C>G

ENST00000619186.4:c.532C>G

ENST00000619485.4:c.892C>G

ENST00000620739.4:c.892C>G

ENST00000622645.4:c.*116C>G

ENST00000635293.1:c.892C>G

NM_000546.5:c.1009C>G

NM_001126112.2:c.1009C>G

NM_001126113.2:c.*28C>G

NM_001126114.2:c.*116C>G

NM_001126115.1:c.613C>G

NM_001126116.1:c.*116C>G

NM_001126117.1:c.*28C>G

NM_001126118.1:c.892C>G

NM_001276695.1:c.*28C>G

NM_001276696.1:c.*116C>G

NM_001276697.1:c.532C>G

NM_001276698.1:c.*116C>G

NM_001276699.1:c.*28C>G

NM_001276760.1:c.892C>G

NM_001276761.1:c.892C>G

NM_001276695.2:c.*28C>G

NM_001276696.2:c.*116C>G

NM_001276697.2:c.532C>G

NM_001276698.2:c.*116C>G

NM_001276699.2:c.*28C>G

NM_001276760.2:c.892C>G

NM_001276761.2:c.892C>G

NM_001126112.3:c.1009C>G

NM_001126113.3:c.*28C>G

NM_001126114.3:c.*116C>G

NM_001126115.2:c.613C>G

NM_001126116.2:c.*116C>G

NM_001126117.2:c.*28C>G

NM_001126118.2:c.892C>G

NM_001276695.3:c.*28C>G

NM_001276696.3:c.*116C>G

NM_001276697.3:c.532C>G

NM_001276698.3:c.*116C>G

NM_001276699.3:c.*28C>G

NM_001276760.3:c.892C>G

NM_001276761.3:c.892C>G

Likely Pathogenic

BP4 PS3 PM2_Supporting PP4 PM5_Supporting

PM1 BA1 BS2 BS4 BS3 BS1 PS4 PS2 PP1 PP3

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 2.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The NM_000546.6(TP53):c.1009C>G variant in TP53 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 337 (p.Arg337Gly). This variant has an allele frequency of 0.000001545 (1/647194 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). This variant received a total of 0.5 point in one proband. (PS4 not met; Internal lab contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor). 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). Computational predictor scores (BayesDel = 0.157822; Align GVGD Class C35) 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). Three missense variants (p.Arg337Ser, p.Arg337Pro, p.Arg337Leu) in the same codon have 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: PS3, BP4, PM2_Supporting, PM5_Supporting, PP4. (Bayesian Points: 6; VCEP specifications version 2.3)

BP4

Computational predictor scores (BayesDel = 0.157822; Align GVGD Class C35) 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).

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 0.000001545 (1/647194 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting).

PP4

At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor).

PM5_Supporting

Three missense variants (p.Arg337Ser, p.Arg337Pro, p.Arg337Leu), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting).

PM1