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_000546.6(TP53):c.997C>T (p.Arg333Cys)

CA000530

184745 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4bdb59d3-0848-40a4-91d8-1adc8f8effef
Approved on: 2025-02-06
Published on: 2025-02-07

HGVS expressions

NM_000546.6:c.997C>T
NM_000546.6(TP53):c.997C>T (p.Arg333Cys)
NC_000017.11:g.7670712G>A
CM000679.2:g.7670712G>A
NC_000017.10:g.7574030G>A
CM000679.1:g.7574030G>A
NC_000017.9:g.7514755G>A
NG_017013.2:g.21839C>T
ENST00000503591.2:c.997C>T
ENST00000508793.6:c.997C>T
ENST00000509690.6:c.601C>T
ENST00000514944.6:c.718C>T
ENST00000604348.6:c.976C>T
ENST00000269305.9:c.997C>T
ENST00000269305.8:c.997C>T
ENST00000359597.8:c.993+2823C>T
ENST00000413465.6:c.782+3469C>T
ENST00000420246.6:c.*104C>T
ENST00000445888.6:c.997C>T
ENST00000455263.6:c.*16C>T
ENST00000504290.5:c.*16C>T
ENST00000504937.5:c.601C>T
ENST00000510385.5:c.*104C>T
ENST00000576024.1:c.54-1022C>T
ENST00000610292.4:c.880C>T
ENST00000610538.4:c.*16C>T
ENST00000610623.4:c.*16C>T
ENST00000615910.4:c.964C>T
ENST00000617185.4:c.*104C>T
ENST00000618944.4:c.*104C>T
ENST00000619186.4:c.520C>T
ENST00000619485.4:c.880C>T
ENST00000620739.4:c.880C>T
ENST00000622645.4:c.*104C>T
ENST00000635293.1:c.880C>T
NM_000546.5:c.997C>T
NM_001126112.2:c.997C>T
NM_001126113.2:c.*16C>T
NM_001126114.2:c.*104C>T
NM_001126115.1:c.601C>T
NM_001126116.1:c.*104C>T
NM_001126117.1:c.*16C>T
NM_001126118.1:c.880C>T
NM_001276695.1:c.*16C>T
NM_001276696.1:c.*104C>T
NM_001276697.1:c.520C>T
NM_001276698.1:c.*104C>T
NM_001276699.1:c.*16C>T
NM_001276760.1:c.880C>T
NM_001276761.1:c.880C>T
NM_001276695.2:c.*16C>T
NM_001276696.2:c.*104C>T
NM_001276697.2:c.520C>T
NM_001276698.2:c.*104C>T
NM_001276699.2:c.*16C>T
NM_001276760.2:c.880C>T
NM_001276761.2:c.880C>T
NM_001126112.3:c.997C>T
NM_001126113.3:c.*16C>T
NM_001126114.3:c.*104C>T
NM_001126115.2:c.601C>T
NM_001126116.2:c.*104C>T
NM_001126117.2:c.*16C>T
NM_001126118.2:c.880C>T
NM_001276695.3:c.*16C>T
NM_001276696.3:c.*104C>T
NM_001276697.3:c.520C>T
NM_001276698.3:c.*104C>T
NM_001276699.3:c.*16C>T
NM_001276760.3:c.880C>T
NM_001276761.3:c.880C>T
More

Likely Benign

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

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6: 997C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 333 (p.Arg333Cys). This variant was observed in an individual with breast cancer in their 20s who also had a VUS in the ATM gene. This variant has also been observed in 44 individuals that did not appear to have LFS across two commercial laboratories (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; Internal lab contributors). This variant has an allele frequency of 0.00001797 (29/1613610alleles) 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, 30224644). Computational predictor scores (BayesDel = 0.237; Align GVGD = Class 35) 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
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; Internal lab contributors).
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, 30224644).
showed comparable or higher expression levels of CDKN1A, MDM2, GADD45A and PMAIP1 compared to WT condition PubMed:39060302
PM2_Supporting
This variant has an allele frequency of 0.00001797 (29/1613610alleles) 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).
PP3
Computational predictor scores (BayesDel = 0.237; Align GVGD = Class 35) 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
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
This variant was observed in an individual with breast cancer in their 20s who also had a VUS in the ATM gene. This variant has also been observed in 44 individuals that did not appear to have LFS across two commercial laboratories (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 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).
PM5
Another missense variant(c.998G>A, p.Arg333His) in the same codon has been reported (ClinVar Variation ID: 142273). However, this variant is classified as likely benign 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
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
Curation History
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