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_001126115.1(TP53):c.182A>C (p.His61Pro)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA16603033

376612 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b7079914-1dfb-4bb9-8f67-f466a0532ac1

Approved on: 2024-08-05

Published on: 2024-08-05

HGVS expressions

NM_001126115.1:c.182A>C

NM_001126115.1(TP53):c.182A>C (p.His61Pro)

NC_000017.11:g.7674953T>G

CM000679.2:g.7674953T>G

NC_000017.10:g.7578271T>G

CM000679.1:g.7578271T>G

NC_000017.9:g.7518996T>G

NG_017013.2:g.17598A>C

ENST00000503591.2:c.578A>C

ENST00000508793.6:c.578A>C

ENST00000509690.6:c.182A>C

ENST00000514944.6:c.299A>C

ENST00000604348.6:c.557A>C

ENST00000269305.9:c.578A>C

ENST00000269305.8:c.578A>C

ENST00000359597.8:c.578A>C

ENST00000413465.6:c.578A>C

ENST00000420246.6:c.578A>C

ENST00000445888.6:c.578A>C

ENST00000455263.6:c.578A>C

ENST00000504290.5:c.182A>C

ENST00000504937.5:c.182A>C

ENST00000505014.5:n.834A>C

ENST00000509690.5:c.182A>C

ENST00000510385.5:c.182A>C

ENST00000514944.5:c.299A>C

ENST00000574684.1:n.67+100A>C

ENST00000610292.4:c.461A>C

ENST00000610538.4:c.461A>C

ENST00000610623.4:c.101A>C

ENST00000615910.4:c.545A>C

ENST00000617185.4:c.578A>C

ENST00000618944.4:c.101A>C

ENST00000619186.4:c.101A>C

ENST00000619485.4:c.461A>C

ENST00000620739.4:c.461A>C

ENST00000622645.4:c.461A>C

ENST00000635293.1:c.461A>C

NM_000546.5:c.578A>C

NM_001126112.2:c.578A>C

NM_001126113.2:c.578A>C

NM_001126114.2:c.578A>C

NM_001126116.1:c.182A>C

NM_001126117.1:c.182A>C

NM_001126118.1:c.461A>C

NM_001276695.1:c.461A>C

NM_001276696.1:c.461A>C

NM_001276697.1:c.101A>C

NM_001276698.1:c.101A>C

NM_001276699.1:c.101A>C

NM_001276760.1:c.461A>C

NM_001276761.1:c.461A>C

NM_001276695.2:c.461A>C

NM_001276696.2:c.461A>C

NM_001276697.2:c.101A>C

NM_001276698.2:c.101A>C

NM_001276699.2:c.101A>C

NM_001276760.2:c.461A>C

NM_001276761.2:c.461A>C

NM_000546.6:c.578A>C

NM_001126112.3:c.578A>C

NM_001126113.3:c.578A>C

NM_001126114.3:c.578A>C

NM_001126115.2:c.182A>C

NM_001126116.2:c.182A>C

NM_001126117.2:c.182A>C

NM_001126118.2:c.461A>C

NM_001276695.3:c.461A>C

NM_001276696.3:c.461A>C

NM_001276697.3:c.101A>C

NM_001276698.3:c.101A>C

NM_001276699.3:c.101A>C

NM_001276760.3:c.461A>C

NM_001276761.3:c.461A>C

Pathogenic

PM1_Supporting PP3_Moderate PS2 PS3 PP4 PM2_Supporting

PVS1 BA1 BS4 BS3 BS1 BS2 BP7 BP4 PS1 PS4 PP1 PM5

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.578A>C variant in TP53 is a missense variant predicted to cause substitution of histidine by proline at amino acid 193 (p.His193Pro). In vitro assays performed in yeast and human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.5922; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618). At least one individual with this variant was found to have a variant allele fraction of 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: SCV002651939.1). This variant has an allele frequency of 6.196e-7 (1/1614048 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). 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: PS3, PP3_Moderate, PS2, PP4, PM2_Supporting, PM1_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024)

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).

PP3_Moderate

Computational predictor scores (BayesDel = 0.5922; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).

PS2

This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly-associated LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 19556618).

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 (PMIDs: 12826609, 30224644, 29979965) (PS3).

PP4

At least one individual with this variant was found to have a variant allele fraction of 25-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributor: SCV002651939.1).

PM2_Supporting

This variant has an allele frequency of 6.196e-7 (1/1614048 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).

PVS1