The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


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

CA16603033

376612 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
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
More

Pathogenic

Met criteria codes 6
PP3_Moderate PS2 PS3 PM1_Supporting PM2_Supporting PP4
Not Met criteria codes 12
BA1 BS2 BS4 BS3 BS1 PS1 PS4 BP7 BP4 PVS1 PP1 PM5

Evidence Links 0

Expert Panel

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)
Met criteria codes
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).
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).
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).
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).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant received a total of 0.5 points across 1 unrelated family. (PS4 not met; PMID: 28369373).
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
6 different missense variants (p.His193Gln; p.His193Leu; p.His193Arg; p.His193Asn; p.His193Asp; p.His193Tyr) in the same codon have been reported (ClinVar Variation IDs: 825975, 185822, 184979, 376614, 376613, 230256). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
Curation History
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