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_001126112.2(TP53):c.907A>G (p.Ser303Gly)

CA000491

142332 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 481b1f30-a3cc-4e41-8fac-e657737c7811
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_001126112.2:c.907A>G
NM_001126112.2(TP53):c.907A>G (p.Ser303Gly)
NC_000017.11:g.7673713T>C
CM000679.2:g.7673713T>C
NC_000017.10:g.7577031T>C
CM000679.1:g.7577031T>C
NC_000017.9:g.7517756T>C
NG_017013.2:g.18838A>G
ENST00000503591.2:c.907A>G
ENST00000508793.6:c.907A>G
ENST00000509690.6:c.511A>G
ENST00000514944.6:c.628A>G
ENST00000604348.6:c.886A>G
ENST00000269305.9:c.907A>G
ENST00000269305.8:c.907A>G
ENST00000359597.8:c.907A>G
ENST00000413465.6:c.782+468A>G
ENST00000420246.6:c.907A>G
ENST00000445888.6:c.907A>G
ENST00000455263.6:c.907A>G
ENST00000504290.5:c.511A>G
ENST00000504937.5:c.511A>G
ENST00000509690.5:c.511A>G
ENST00000510385.5:c.511A>G
ENST00000610292.4:c.790A>G
ENST00000610538.4:c.790A>G
ENST00000610623.4:c.430A>G
ENST00000615910.4:c.874A>G
ENST00000617185.4:c.907A>G
ENST00000618944.4:c.430A>G
ENST00000619186.4:c.430A>G
ENST00000619485.4:c.790A>G
ENST00000620739.4:c.790A>G
ENST00000622645.4:c.790A>G
ENST00000635293.1:c.790A>G
NM_000546.5:c.907A>G
NM_001126113.2:c.907A>G
NM_001126114.2:c.907A>G
NM_001126115.1:c.511A>G
NM_001126116.1:c.511A>G
NM_001126117.1:c.511A>G
NM_001126118.1:c.790A>G
NM_001276695.1:c.790A>G
NM_001276696.1:c.790A>G
NM_001276697.1:c.430A>G
NM_001276698.1:c.430A>G
NM_001276699.1:c.430A>G
NM_001276760.1:c.790A>G
NM_001276761.1:c.790A>G
NM_001276695.2:c.790A>G
NM_001276696.2:c.790A>G
NM_001276697.2:c.430A>G
NM_001276698.2:c.430A>G
NM_001276699.2:c.430A>G
NM_001276760.2:c.790A>G
NM_001276761.2:c.790A>G
NM_000546.6:c.907A>G
NM_001126112.3:c.907A>G
NM_001126113.3:c.907A>G
NM_001126114.3:c.907A>G
NM_001126115.2:c.511A>G
NM_001126116.2:c.511A>G
NM_001126117.2:c.511A>G
NM_001126118.2:c.790A>G
NM_001276695.3:c.790A>G
NM_001276696.3:c.790A>G
NM_001276697.3:c.430A>G
NM_001276698.3:c.430A>G
NM_001276699.3:c.430A>G
NM_001276760.3:c.790A>G
NM_001276761.3:c.790A>G
More

Likely Benign

Met criteria codes 3
BP4 PM2_Supporting BS3
Not Met criteria codes 22
PS2 PS4 PS3 PS1 BP3 BP2 BP1 BP5 BP7 BA1 PP4 PP1 PP3 PP2 PM4 PM1 PM5 PM6 PVS1 BS2 BS4 BS1

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: c.907A>G variant in TP53 is a missense variant predicted to cause substitution of serine by glycine at amino acid 303 (p.Ser303Gly). This variant has an allele frequency of 0.000002542 (3/1180040 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). Computational predictor scores (BayesDel = -0.0726; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). 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: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.2; 1/16/2025).
Met criteria codes
BP4
BP4_MODERATE Computational predictor scores (BayesDel = -0.0726; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate).
PM2_Supporting
This variant has an allele frequency of 0.000002542 (3/1180040 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).
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).
No Kotler data for variant PubMed:29979965
Not Met criteria codes
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Observed 9+ times across clinical laboratories with no informative cases.
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
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
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
BP7
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
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Observed 9+ times across clinical laboratories with no informative cases.
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
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
Two different missense variants (p.Ser303Arg, p.Ser303Asn) in the same codon have been reported (ClinVar Variation ID 1024359, 230695). However, the variants have not yet been curated to determine if they would be classified as pathogenic or likely pathogenic by the ClinGen TP53 VCEP’s specifications (PM5 not evaluated).
PM6
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
BS2
Observed 9+ times across clinical laboratories with no informative cases.
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
Curation History
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