Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000546.5(TP53):c.743G>T (p.Arg248Leu)

CA10580924

230253 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 291eceb4-ecb0-489a-b637-b9ff4f5f34d5
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.743G>T
NM_000546.5(TP53):c.743G>T (p.Arg248Leu)
NC_000017.11:g.7674220C>A
CM000679.2:g.7674220C>A
NC_000017.10:g.7577538C>A
CM000679.1:g.7577538C>A
NC_000017.9:g.7518263C>A
NG_017013.2:g.18331G>T
ENST00000503591.2:c.743G>T
ENST00000508793.6:c.743G>T
ENST00000509690.6:c.347G>T
ENST00000514944.6:c.464G>T
ENST00000604348.6:c.722G>T
ENST00000269305.9:c.743G>T
ENST00000269305.8:c.743G>T
ENST00000359597.8:c.743G>T
ENST00000413465.6:c.743G>T
ENST00000420246.6:c.743G>T
ENST00000445888.6:c.743G>T
ENST00000455263.6:c.743G>T
ENST00000504290.5:c.347G>T
ENST00000504937.5:c.347G>T
ENST00000509690.5:c.347G>T
ENST00000510385.5:c.347G>T
ENST00000514944.5:c.464G>T
ENST00000610292.4:c.626G>T
ENST00000610538.4:c.626G>T
ENST00000610623.4:c.266G>T
ENST00000615910.4:c.710G>T
ENST00000617185.4:c.743G>T
ENST00000618944.4:c.266G>T
ENST00000619186.4:c.266G>T
ENST00000619485.4:c.626G>T
ENST00000620739.4:c.626G>T
ENST00000622645.4:c.626G>T
ENST00000635293.1:c.626G>T
NM_001126112.2:c.743G>T
NM_001126113.2:c.743G>T
NM_001126114.2:c.743G>T
NM_001126115.1:c.347G>T
NM_001126116.1:c.347G>T
NM_001126117.1:c.347G>T
NM_001126118.1:c.626G>T
NM_001276695.1:c.626G>T
NM_001276696.1:c.626G>T
NM_001276697.1:c.266G>T
NM_001276698.1:c.266G>T
NM_001276699.1:c.266G>T
NM_001276760.1:c.626G>T
NM_001276761.1:c.626G>T
NM_001276695.2:c.626G>T
NM_001276696.2:c.626G>T
NM_001276697.2:c.266G>T
NM_001276698.2:c.266G>T
NM_001276699.2:c.266G>T
NM_001276760.2:c.626G>T
NM_001276761.2:c.626G>T
NM_000546.6:c.743G>T
NM_001126112.3:c.743G>T
NM_001126113.3:c.743G>T
NM_001126114.3:c.743G>T
NM_001126115.2:c.347G>T
NM_001126116.2:c.347G>T
NM_001126117.2:c.347G>T
NM_001126118.2:c.626G>T
NM_001276695.3:c.626G>T
NM_001276696.3:c.626G>T
NM_001276697.3:c.266G>T
NM_001276698.3:c.266G>T
NM_001276699.3:c.266G>T
NM_001276760.3:c.626G>T
NM_001276761.3:c.626G>T

Pathogenic

Met criteria codes 9
PP3_Moderate PS3 PP4_Moderate PM5_Strong PM2_Supporting PS4_Supporting PS2_Supporting PP1 PM1
Not Met criteria codes 7
PS1 BP4 BA1 BS2 BS4 BS3 BS1

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.743G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 248 (p.Arg248Leu). This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of of 1-1.5 points. (PS4_Supporting; PMIDs 1359493, 25584008, ClinVar SCV SCV000273723.7, Internal lab contributor). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal lab contributors: SCV000273723.7). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 1359493). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000273723.7). 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). Two different missense variants, c.743G>A; p.Arg248Gln and c.742C>T; p.Arg248Trp, ClinVar IDs 12347 and 12356, in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5_Strong). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Computational predictor scores (BayesDel = 0.570318; 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). In summary, TP53 c.743G>T; p.Arg248Leu meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PS2_Supporting, PP1, PP4_Moderate, PS3, PM5_Strong, PM1, PM2_Supporting, PP3_Moderate. (Bayesian Points: 18; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PP3_Moderate
Computational predictor scores (BayesDel = 0.570318; 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).
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_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors: SCV000273723.7).
PM5_Strong
Two different missense variants, c.743G>A; p.Arg248Gln and c.742C>T; p.Arg248Trp, ClinVar IDs 12347 and 12356, in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5_Strong).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
PS4_Supporting
This variant has been reported in 3 unrelated probands meeting Revised Chompret criteria, respectively. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of of 1-1.5 points. (PS4_Supporting; PMIDs 1359493, 25584008, ClinVar SCV SCV000273723.7, Internal lab contributor).
PS2_Supporting
This variant has been identified as a de novo occurrence with unconfirmed parental relationships in an individual with a moderately LFS-associated cancer totaling 1 phenotype point (PS2_Supporting; Internal lab contributors: SCV000273723.7).
PP1
The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 1359493).
PM1
This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PMID: 8023157 ) (PM1).
Not Met criteria codes
PS1
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
Absent in FLOSSIES.
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
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