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_001276761.1:c.311T>C

CA397842518

804214 (ClinVar)

Gene: TP53 (HGNC:7157)

Condition: Li-Fraumeni syndrome (MONDO:0018875)

Inheritance Mode: Autosomal dominant inheritance

UUID: 96976462-a14e-41e1-9dc6-73aa6108c844

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_001276761.1:c.311T>C

NC_000017.11:g.7675184A>G

CM000679.2:g.7675184A>G

NC_000017.10:g.7578502A>G

CM000679.1:g.7578502A>G

NC_000017.9:g.7519227A>G

NG_017013.2:g.17367T>C

ENST00000503591.2:c.428T>C

ENST00000508793.6:c.428T>C

ENST00000509690.6:c.32T>C

ENST00000514944.6:c.149T>C

ENST00000604348.6:c.407T>C

ENST00000269305.9:c.428T>C

ENST00000269305.8:c.428T>C

ENST00000359597.8:c.428T>C

ENST00000413465.6:c.428T>C

ENST00000420246.6:c.428T>C

ENST00000445888.6:c.428T>C

ENST00000455263.6:c.428T>C

ENST00000504290.5:c.32T>C

ENST00000504937.5:c.32T>C

ENST00000505014.5:n.684T>C

ENST00000508793.5:c.428T>C

ENST00000509690.5:c.32T>C

ENST00000510385.5:c.32T>C

ENST00000514944.5:c.149T>C

ENST00000604348.5:c.407T>C

ENST00000610292.4:c.311T>C

ENST00000610538.4:c.311T>C

ENST00000610623.4:c.-50T>C

ENST00000615910.4:c.395T>C

ENST00000617185.4:c.428T>C

ENST00000618944.4:c.-50T>C

ENST00000619186.4:c.-50T>C

ENST00000619485.4:c.311T>C

ENST00000620739.4:c.311T>C

ENST00000622645.4:c.311T>C

ENST00000635293.1:c.311T>C

NM_000546.5:c.428T>C

NM_001126112.2:c.428T>C

NM_001126113.2:c.428T>C

NM_001126114.2:c.428T>C

NM_001126115.1:c.32T>C

NM_001126116.1:c.32T>C

NM_001126117.1:c.32T>C

NM_001126118.1:c.311T>C

NM_001276695.1:c.311T>C

NM_001276696.1:c.311T>C

NM_001276697.1:c.-50T>C

NM_001276698.1:c.-50T>C

NM_001276699.1:c.-50T>C

NM_001276760.1:c.311T>C

NM_001276695.2:c.311T>C

NM_001276696.2:c.311T>C

NM_001276697.2:c.-50T>C

NM_001276698.2:c.-50T>C

NM_001276699.2:c.-50T>C

NM_001276760.2:c.311T>C

NM_001276761.2:c.311T>C

NM_000546.6:c.428T>C

NM_001126112.3:c.428T>C

NM_001126113.3:c.428T>C

NM_001126114.3:c.428T>C

NM_001126115.2:c.32T>C

NM_001126116.2:c.32T>C

NM_001126117.2:c.32T>C

NM_001126118.2:c.311T>C

NM_001276695.3:c.311T>C

NM_001276696.3:c.311T>C

NM_001276697.3:c.-50T>C

NM_001276698.3:c.-50T>C

NM_001276699.3:c.-50T>C

NM_001276760.3:c.311T>C

NM_001276761.3:c.311T>C

Pathogenic

PM1_Supporting PS2 PS3 PP3 PM2_Supporting

PS4 PS1 PP4 PM5 BA1 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.428T>C variant in TP53 is a missense variant predicted to cause substitution of Valine by Alanine at amino acid 143 (p.Val143Ala). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 6 phenotype points (PS2; PMID: 19701813, 25318593). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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 = 0.1806; 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 7 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot critical functional domain 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: PS2, PM2_Supporting, PS3, PP3, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.0; 7/24/2024).

PM1_Supporting

This variant has 7 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspotcritical functional domain by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).

PS2

This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with an LFS-associated cancer totaling 6 phenotype points (PS2; PMID: 19701813, 25318593).

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).

PP3

Computational predictor scores (BayesDel = 0.1806; 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).

PM2_Supporting

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

PS4

This variant received a total of 1 point across 2 unrelated probands. However, PS4 cannot be applied because these were both de novo cases counted towards PS2. (PS4 not met; PMIDs: 29070607, 19701813).

PS1