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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  • 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.847C>T (p.Arg283Cys)

CA000457

127824 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0b9a7a17-b7b8-4223-bd64-69617a2d691d
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.847C>T
NM_000546.5(TP53):c.847C>T (p.Arg283Cys)
NC_000017.11:g.7673773G>A
CM000679.2:g.7673773G>A
NC_000017.10:g.7577091G>A
CM000679.1:g.7577091G>A
NC_000017.9:g.7517816G>A
NG_017013.2:g.18778C>T
ENST00000503591.2:c.847C>T
ENST00000508793.6:c.847C>T
ENST00000509690.6:c.451C>T
ENST00000514944.6:c.568C>T
ENST00000604348.6:c.826C>T
ENST00000269305.9:c.847C>T
ENST00000269305.8:c.847C>T
ENST00000359597.8:c.847C>T
ENST00000413465.6:c.782+408C>T
ENST00000420246.6:c.847C>T
ENST00000445888.6:c.847C>T
ENST00000455263.6:c.847C>T
ENST00000504290.5:c.451C>T
ENST00000504937.5:c.451C>T
ENST00000509690.5:c.451C>T
ENST00000510385.5:c.451C>T
ENST00000610292.4:c.730C>T
ENST00000610538.4:c.730C>T
ENST00000610623.4:c.370C>T
ENST00000615910.4:c.814C>T
ENST00000617185.4:c.847C>T
ENST00000618944.4:c.370C>T
ENST00000619186.4:c.370C>T
ENST00000619485.4:c.730C>T
ENST00000620739.4:c.730C>T
ENST00000622645.4:c.730C>T
ENST00000635293.1:c.730C>T
NM_001126112.2:c.847C>T
NM_001126113.2:c.847C>T
NM_001126114.2:c.847C>T
NM_001126115.1:c.451C>T
NM_001126116.1:c.451C>T
NM_001126117.1:c.451C>T
NM_001126118.1:c.730C>T
NM_001276695.1:c.730C>T
NM_001276696.1:c.730C>T
NM_001276697.1:c.370C>T
NM_001276698.1:c.370C>T
NM_001276699.1:c.370C>T
NM_001276760.1:c.730C>T
NM_001276761.1:c.730C>T
NM_001276695.2:c.730C>T
NM_001276696.2:c.730C>T
NM_001276697.2:c.370C>T
NM_001276698.2:c.370C>T
NM_001276699.2:c.370C>T
NM_001276760.2:c.730C>T
NM_001276761.2:c.730C>T
NM_000546.6:c.847C>T
NM_001126112.3:c.847C>T
NM_001126113.3:c.847C>T
NM_001126114.3:c.847C>T
NM_001126115.2:c.451C>T
NM_001126116.2:c.451C>T
NM_001126117.2:c.451C>T
NM_001126118.2:c.730C>T
NM_001276695.3:c.730C>T
NM_001276696.3:c.730C>T
NM_001276697.3:c.370C>T
NM_001276698.3:c.370C>T
NM_001276699.3:c.370C>T
NM_001276760.3:c.730C>T
NM_001276761.3:c.730C>T

Likely Benign

Met criteria codes 4
PM5_Supporting BS3 BS2 PP3
Not Met criteria codes 15
PM2 BA1 PM3 PM1 BS1 BP5 BP2 BP4 PVS1 PS2 PS1 PS4 PS3 PP4 PP1

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.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) 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). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024)
Met criteria codes
PM5_Supporting
Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting).
BS3
In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644).
BS2
This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8).
PP3
Computational predictor scores (BayesDel = 0.33; Align GVGD = Class C55) 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).
Not Met criteria codes
PM2
The highest population minor allele frequency in gnomAD v41.0 is 0.00008559 (101/1180022 alleles) in the European (non-Finnish) population (PM2, BS1, and BA1 are not met).
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
This variant does not reside within a region of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1 not met).
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
This variant was found in one woman with breast cancer at 29 and ovarian cancer at 56 who also had a pathogenic variant in BRCA2, but this does not rule out the pathogencity of this variant.
BP2
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
PS2
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 has been reported in 3 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributor: SCV000183772.8). PS4 not applied as PM2_Supporting not applied.
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
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