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]
  • 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_000546.5(TP53):c.742C>T (p.Arg248Trp)

CA000382

12347 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 55c3283e-f0f6-4e18-b837-99a275ea7d90
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.742C>T
NM_000546.5(TP53):c.742C>T (p.Arg248Trp)
NC_000017.11:g.7674221G>A
CM000679.2:g.7674221G>A
NC_000017.10:g.7577539G>A
CM000679.1:g.7577539G>A
NC_000017.9:g.7518264G>A
NG_017013.2:g.18330C>T
ENST00000503591.2:c.742C>T
ENST00000508793.6:c.742C>T
ENST00000509690.6:c.346C>T
ENST00000514944.6:c.463C>T
ENST00000604348.6:c.721C>T
ENST00000269305.9:c.742C>T
ENST00000269305.8:c.742C>T
ENST00000359597.8:c.742C>T
ENST00000413465.6:c.742C>T
ENST00000420246.6:c.742C>T
ENST00000445888.6:c.742C>T
ENST00000455263.6:c.742C>T
ENST00000504290.5:c.346C>T
ENST00000504937.5:c.346C>T
ENST00000509690.5:c.346C>T
ENST00000510385.5:c.346C>T
ENST00000514944.5:c.463C>T
ENST00000610292.4:c.625C>T
ENST00000610538.4:c.625C>T
ENST00000610623.4:c.265C>T
ENST00000615910.4:c.709C>T
ENST00000617185.4:c.742C>T
ENST00000618944.4:c.265C>T
ENST00000619186.4:c.265C>T
ENST00000619485.4:c.625C>T
ENST00000620739.4:c.625C>T
ENST00000622645.4:c.625C>T
ENST00000635293.1:c.625C>T
NM_001126112.2:c.742C>T
NM_001126113.2:c.742C>T
NM_001126114.2:c.742C>T
NM_001126115.1:c.346C>T
NM_001126116.1:c.346C>T
NM_001126117.1:c.346C>T
NM_001126118.1:c.625C>T
NM_001276695.1:c.625C>T
NM_001276696.1:c.625C>T
NM_001276697.1:c.265C>T
NM_001276698.1:c.265C>T
NM_001276699.1:c.265C>T
NM_001276760.1:c.625C>T
NM_001276761.1:c.625C>T
NM_001276695.2:c.625C>T
NM_001276696.2:c.625C>T
NM_001276697.2:c.265C>T
NM_001276698.2:c.265C>T
NM_001276699.2:c.265C>T
NM_001276760.2:c.625C>T
NM_001276761.2:c.625C>T
NM_000546.6:c.742C>T
NM_001126112.3:c.742C>T
NM_001126113.3:c.742C>T
NM_001126114.3:c.742C>T
NM_001126115.2:c.346C>T
NM_001126116.2:c.346C>T
NM_001126117.2:c.346C>T
NM_001126118.2:c.625C>T
NM_001276695.3:c.625C>T
NM_001276696.3:c.625C>T
NM_001276697.3:c.265C>T
NM_001276698.3:c.265C>T
NM_001276699.3:c.265C>T
NM_001276760.3:c.625C>T
NM_001276761.3:c.625C>T
More

Pathogenic

Met criteria codes 9
PS4 PS2 PS3 PM5 PM1 PP4_Moderate PP3_Moderate PP1_Strong PM2_Supporting
Not Met criteria codes 9
PS1 PVS1 BA1 BS2 BS1 BS4 BS3 BP4 BP5

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.742C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 248 (p.Arg248Trp). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074). This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13). The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456). 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: SCV000212766.7). This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (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 (PMIDs: 12826609, 30224644, 29979965) (PS3). 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). Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications. (PM5). Computational predictor scores (BayesDel = 0.5336; 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, 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, PS4_Very Strong, PP1_Strong, PP4_Moderate, PM2_Supporting, PS3, PM1, PM5, PP3_Moderate. (Bayesian Points: 29; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PS4
PS4_VERY STRONG MET This variant has been reported in >10 unrelated probands meeting Classic and Revised Chompret criteria. Based on this evidence, this variant scores 13.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs: 8527048, 9242456, 20522432, 8425176, 32658383, 9825943, 1978757. Internal lab contributors: SCV000212766.7, SCV000218912.13).
PS2
This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with an LFS-associated cancer totaling four phenotype points (PS2; PMID: 10089074).
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).
PM5
Another missense variant c.743G>A; p.Arg248Gln (ClinVar Variation ID 12356), in the same codon have been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5).
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).
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: SCV000212766.7).
PP3_Moderate
Computational predictor scores (BayesDel = 0.5336; 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).
PP1_Strong
The variant has been reported to segregate with LFS-associated cancers in ≥ 7 meioses in six families (PP1_Strong; PMID: 8527048, 9825943, 8527048, 1978757, 9825943, 9242456).
PM2_Supporting
This variant has an allele frequency of 0.000005933 (7/1179814 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
Not Met criteria codes
PS1
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
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
BS1
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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