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 computed assertion could be determined for this classification!

Variant: NM_000546.5(TP53):c.1003C>T (p.Arg335Cys)

CA000009

141159 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 2c051651-783e-433a-913d-2201e71b6cb7
Approved on: 2025-02-06
Published on: 2025-02-07

HGVS expressions

NM_000546.5:c.1003C>T
NM_000546.5(TP53):c.1003C>T (p.Arg335Cys)
NC_000017.11:g.7670706G>A
CM000679.2:g.7670706G>A
NC_000017.10:g.7574024G>A
CM000679.1:g.7574024G>A
NC_000017.9:g.7514749G>A
NG_017013.2:g.21845C>T
ENST00000503591.2:c.1003C>T
ENST00000508793.6:c.1003C>T
ENST00000509690.6:c.607C>T
ENST00000514944.6:c.724C>T
ENST00000604348.6:c.982C>T
ENST00000269305.9:c.1003C>T
ENST00000269305.8:c.1003C>T
ENST00000359597.8:c.993+2829C>T
ENST00000413465.6:c.782+3475C>T
ENST00000420246.6:c.*110C>T
ENST00000445888.6:c.1003C>T
ENST00000455263.6:c.*22C>T
ENST00000504290.5:c.*22C>T
ENST00000504937.5:c.607C>T
ENST00000510385.5:c.*110C>T
ENST00000576024.1:c.54-1016C>T
ENST00000610292.4:c.886C>T
ENST00000610538.4:c.*22C>T
ENST00000610623.4:c.*22C>T
ENST00000615910.4:c.970C>T
ENST00000617185.4:c.*110C>T
ENST00000618944.4:c.*110C>T
ENST00000619186.4:c.526C>T
ENST00000619485.4:c.886C>T
ENST00000620739.4:c.886C>T
ENST00000622645.4:c.*110C>T
ENST00000635293.1:c.886C>T
NM_001126112.2:c.1003C>T
NM_001126113.2:c.*22C>T
NM_001126114.2:c.*110C>T
NM_001126115.1:c.607C>T
NM_001126116.1:c.*110C>T
NM_001126117.1:c.*22C>T
NM_001126118.1:c.886C>T
NM_001276695.1:c.*22C>T
NM_001276696.1:c.*110C>T
NM_001276697.1:c.526C>T
NM_001276698.1:c.*110C>T
NM_001276699.1:c.*22C>T
NM_001276760.1:c.886C>T
NM_001276761.1:c.886C>T
NM_001276695.2:c.*22C>T
NM_001276696.2:c.*110C>T
NM_001276697.2:c.526C>T
NM_001276698.2:c.*110C>T
NM_001276699.2:c.*22C>T
NM_001276760.2:c.886C>T
NM_001276761.2:c.886C>T
NM_000546.6:c.1003C>T
NM_001126112.3:c.1003C>T
NM_001126113.3:c.*22C>T
NM_001126114.3:c.*110C>T
NM_001126115.2:c.607C>T
NM_001126116.2:c.*110C>T
NM_001126117.2:c.*22C>T
NM_001126118.2:c.886C>T
NM_001276695.3:c.*22C>T
NM_001276696.3:c.*110C>T
NM_001276697.3:c.526C>T
NM_001276698.3:c.*110C>T
NM_001276699.3:c.*22C>T
NM_001276760.3:c.886C>T
NM_001276761.3:c.886C>T
More

Likely Benign

Met criteria codes 4
BS3 PM2_Supporting BS2_Supporting PP3
Not Met criteria codes 12
PM1 PM5 BA1 BS4 BS1 BP4 PS2 PS4 PS3 PS1 PP1 PP4

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 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: c.1003C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 335 (p.Arg335Cys). Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors). This variant has been observed in 2-3 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_Supporting; ClinVar SCV: SCV000629764.4). This variant has an allele frequency of 0.000001859 (3/1613806 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). 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 = 0.275; Align GVGD = Class C25) 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). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, PP3. (Bayesian Points: -3; VCEP specifications version 2.2; 2/6/2025).
Met criteria codes
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).
PM2_Supporting
This variant has an allele frequency of 0.000001859 (3/1613806 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting).
BS2_Supporting
This variant has been observed in 2-3 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_Supporting; ClinVar SCV: SCV000629764.4).
PP3
Computational predictor scores (BayesDel = 0.275; Align GVGD = Class C25) 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
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).
PM5
3 different missense variants (p.Arg335Leu, p.Arg335Pro, p.Arg335His) in the same codon have been reported. However, these variants have not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not met).
BA1
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
BS1
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
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Although this variant has been observed in germline cases, to our knowledge, this variant has not been reported in individuals meeting classical LFS or Chompret criteria (PS4 not met; Internal lab contributors)
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No other variants with same amino acid change in ClinVar
PP1
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
Curation History
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