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.1000G>C (p.Gly334Arg)

CA000007

182969 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 92e57f24-9a2a-4d40-9b02-5284485e54b9
Approved on: 2024-08-05
Published on: 2024-08-05

HGVS expressions

NM_000546.5:c.1000G>C
NM_000546.5(TP53):c.1000G>C (p.Gly334Arg)
NC_000017.11:g.7670709C>G
CM000679.2:g.7670709C>G
NC_000017.10:g.7574027C>G
CM000679.1:g.7574027C>G
NC_000017.9:g.7514752C>G
NG_017013.2:g.21842G>C
ENST00000503591.2:c.1000G>C
ENST00000508793.6:c.1000G>C
ENST00000509690.6:c.604G>C
ENST00000514944.6:c.721G>C
ENST00000604348.6:c.979G>C
ENST00000269305.9:c.1000G>C
ENST00000269305.8:c.1000G>C
ENST00000359597.8:c.993+2826G>C
ENST00000413465.6:c.782+3472G>C
ENST00000420246.6:c.*107G>C
ENST00000445888.6:c.1000G>C
ENST00000455263.6:c.*19G>C
ENST00000504290.5:c.*19G>C
ENST00000504937.5:c.604G>C
ENST00000510385.5:c.*107G>C
ENST00000576024.1:c.54-1019G>C
ENST00000610292.4:c.883G>C
ENST00000610538.4:c.*19G>C
ENST00000610623.4:c.*19G>C
ENST00000615910.4:c.967G>C
ENST00000617185.4:c.*107G>C
ENST00000618944.4:c.*107G>C
ENST00000619186.4:c.523G>C
ENST00000619485.4:c.883G>C
ENST00000620739.4:c.883G>C
ENST00000622645.4:c.*107G>C
ENST00000635293.1:c.883G>C
NM_001126112.2:c.1000G>C
NM_001126113.2:c.*19G>C
NM_001126114.2:c.*107G>C
NM_001126115.1:c.604G>C
NM_001126116.1:c.*107G>C
NM_001126117.1:c.*19G>C
NM_001126118.1:c.883G>C
NM_001276695.1:c.*19G>C
NM_001276696.1:c.*107G>C
NM_001276697.1:c.523G>C
NM_001276698.1:c.*107G>C
NM_001276699.1:c.*19G>C
NM_001276760.1:c.883G>C
NM_001276761.1:c.883G>C
NM_001276695.2:c.*19G>C
NM_001276696.2:c.*107G>C
NM_001276697.2:c.523G>C
NM_001276698.2:c.*107G>C
NM_001276699.2:c.*19G>C
NM_001276760.2:c.883G>C
NM_001276761.2:c.883G>C
NM_000546.6:c.1000G>C
NM_001126112.3:c.1000G>C
NM_001126113.3:c.*19G>C
NM_001126114.3:c.*107G>C
NM_001126115.2:c.604G>C
NM_001126116.2:c.*107G>C
NM_001126117.2:c.*19G>C
NM_001126118.2:c.883G>C
NM_001276695.3:c.*19G>C
NM_001276696.3:c.*107G>C
NM_001276697.3:c.523G>C
NM_001276698.3:c.*107G>C
NM_001276699.3:c.*19G>C
NM_001276760.3:c.883G>C
NM_001276761.3:c.883G>C

Uncertain Significance

Met criteria codes 5
BS3 BS2 PS4 PM2_Supporting PP1_Moderate
Not Met criteria codes 11
BS4 BS1 BP4 PS2 PS1 PS3 BA1 PP3 PP4 PM1 PM5

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.1000G>C variant in TP53 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 334 (p.Gly334Arg). This variant has been reported in 11 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 23580068, 25584008, 32675277, Internal lab contributors: SCV000216886.6, SCV000545272.7). The variant has been reported to segregate with LFS-associated cancers in 5 meioses in 3 families (PP1_Moderate; PMIDs: 32675277, Internal contributor). 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; Internal lab contributors: SCV000545272.9). This variant has an allele frequency of 0.000002543 (3/1179822 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 functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). This variant has been reported as a putative low penetrance founder variant in the Ashkenazi Jewish population (PMID:32675277). At this time, the TP53 VCEP cannot curate variants for low-penetrance designation. In summary, this variant is classified as a variant of unknown significance for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PS4, PP1_Moderate, PM2_supporting. (Bayesian Points: -1; VCEP specifications version 2.0; 7/24/2024)
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).
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; Internal lab contributors: SCV000545272.9).
PS4
This variant has been reported in 11 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 5.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 23580068, 25584008, 32675277, Internal lab contributors: SCV000216886.6, SCV000545272.7).
PM2_Supporting
This variant has an allele frequency of 0.000002543 (3/1179822 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).
PP1_Moderate
The variant has been reported to segregate with LFS-associated cancers in 5 meioses in 3 families (PP1_Moderate; PMIDs: 32675277, Internal contributor).
Not Met criteria codes
BS4
In reported families with segregation data none appear to meet BS4 criteria
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0 predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
The same amino acid change, resulting from a different nucleotide change c.1000G>A , has been reported in an individual with HER2+ breast cancer meeting revised Chompret and an individual with adrenocortical carcinoma (PMIDs: 23580068, 25584008, ClinVar Variation ID: 186086 Internal lab contributors: SCV000216350.7, SCV003317580.1). However, this other variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PS1 not met).
PS3
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
PP3
The results from the computational predictors BayesDel and AlignGVGD do not agree, providing no evidence that correlates with a damaging or benign impact on TP53 function via protein change. Additionally, the computational splicing predictor SpliceAI gives a score of 0 predicting that the variant has no impact on splicing (score threshold ≤ 0.10) (PP3 and BP4 not met).
PP4
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
2 different missense variants (c.1001G>A; p.Gly334Glu, c.1000G>T; p.Gly334Trp) in the same codon have been reported (ClinVar Variation ID: 951578, 428876). 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).
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