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.1025G>C (p.Arg342Pro)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA337802

215996 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6596a2a8-f9bc-4bad-b9fb-403dfe19364d

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000546.6:c.1025G>C

NM_000546.6(TP53):c.1025G>C (p.Arg342Pro)

NC_000017.11:g.7670684C>G

CM000679.2:g.7670684C>G

NC_000017.10:g.7574002C>G

CM000679.1:g.7574002C>G

NC_000017.9:g.7514727C>G

NG_017013.2:g.21867G>C

ENST00000503591.2:c.1025G>C

ENST00000508793.6:c.1025G>C

ENST00000509690.6:c.629G>C

ENST00000514944.6:c.746G>C

ENST00000604348.6:c.1004G>C

ENST00000269305.9:c.1025G>C

ENST00000269305.8:c.1025G>C

ENST00000359597.8:c.993+2851G>C

ENST00000413465.6:c.782+3497G>C

ENST00000420246.6:c.*132G>C

ENST00000445888.6:c.1025G>C

ENST00000455263.6:c.*44G>C

ENST00000504290.5:c.*44G>C

ENST00000504937.5:c.629G>C

ENST00000510385.5:c.*132G>C

ENST00000576024.1:c.54-994G>C

ENST00000610292.4:c.908G>C

ENST00000610538.4:c.*44G>C

ENST00000610623.4:c.*44G>C

ENST00000615910.4:c.992G>C

ENST00000617185.4:c.*132G>C

ENST00000618944.4:c.*132G>C

ENST00000619186.4:c.548G>C

ENST00000619485.4:c.908G>C

ENST00000620739.4:c.908G>C

ENST00000622645.4:c.*132G>C

ENST00000635293.1:c.908G>C

NM_000546.5:c.1025G>C

NM_001126112.2:c.1025G>C

NM_001126113.2:c.*44G>C

NM_001126114.2:c.*132G>C

NM_001126115.1:c.629G>C

NM_001126116.1:c.*132G>C

NM_001126117.1:c.*44G>C

NM_001126118.1:c.908G>C

NM_001276695.1:c.*44G>C

NM_001276696.1:c.*132G>C

NM_001276697.1:c.548G>C

NM_001276698.1:c.*132G>C

NM_001276699.1:c.*44G>C

NM_001276760.1:c.908G>C

NM_001276761.1:c.908G>C

NM_001276695.2:c.*44G>C

NM_001276696.2:c.*132G>C

NM_001276697.2:c.548G>C

NM_001276698.2:c.*132G>C

NM_001276699.2:c.*44G>C

NM_001276760.2:c.908G>C

NM_001276761.2:c.908G>C

NM_001126112.3:c.1025G>C

NM_001126113.3:c.*44G>C

NM_001126114.3:c.*132G>C

NM_001126115.2:c.629G>C

NM_001126116.2:c.*132G>C

NM_001126117.2:c.*44G>C

NM_001126118.2:c.908G>C

NM_001276695.3:c.*44G>C

NM_001276696.3:c.*132G>C

NM_001276697.3:c.548G>C

NM_001276698.3:c.*132G>C

NM_001276699.3:c.*44G>C

NM_001276760.3:c.908G>C

NM_001276761.3:c.908G>C

Pathogenic

PS3 PP3 PS4_Moderate PM1_Supporting PP1_Strong PM2_Supporting

PM4 PM5 PS1 PS2 BA1 PP4 PVS1 BS4 BS3 BS1 BS2 BP4

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.1025G>C variant in TP53 is a missense variant predicted to cause substitution of arginine by proline at amino acid 342 (p.Arg342Pro). This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) 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 8 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 Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1_Strong, PS3, PM2_Supporting, PP3, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 9/6/2024)

PS3

In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation, loss of growth suppression activity, and impaired tetramer formation indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 16007150).

PP3

Computational predictor scores (BayesDel = 0.24; Align GVGD = Class C35) 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).

PS4_Moderate

This variant has been reported in 3 unrelated families meeting Classic criteria. Based on this evidence, this variant scores 3 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs 25981898, 25226867, 19714490).

PM1_Supporting

This variant has 8 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).

PP1_Strong

The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses from 3 families (PP1_Strong; PMIDs 25981898, 25226867, 19714490).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PM4