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_001276761.2:c.892C>A

CA397832787

1019612 (ClinVar)

Gene: TP53 (HGNC:7157)
Condition: Li-Fraumeni syndrome (MONDO:0018875)
Inheritance Mode: Autosomal dominant inheritance
UUID: 94981547-1bc0-489e-8b9a-b5963be2d6de
Approved on: 2025-05-07
Published on: 2025-12-05

HGVS expressions

NM_001276761.2:c.892C>A
NC_000017.11:g.7670700G>T
CM000679.2:g.7670700G>T
NC_000017.10:g.7574018G>T
CM000679.1:g.7574018G>T
NC_000017.9:g.7514743G>T
NG_017013.2:g.21851C>A
ENST00000503591.2:c.1009C>A
ENST00000508793.6:c.1009C>A
ENST00000509690.6:c.613C>A
ENST00000514944.6:c.730C>A
ENST00000604348.6:c.988C>A
ENST00000269305.9:c.1009C>A
ENST00000269305.8:c.1009C>A
ENST00000359597.8:c.993+2835C>A
ENST00000413465.6:c.782+3481C>A
ENST00000420246.6:c.*116C>A
ENST00000445888.6:c.1009C>A
ENST00000455263.6:c.*28C>A
ENST00000504290.5:c.*28C>A
ENST00000504937.5:c.613C>A
ENST00000510385.5:c.*116C>A
ENST00000576024.1:c.54-1010C>A
ENST00000610292.4:c.892C>A
ENST00000610538.4:c.*28C>A
ENST00000610623.4:c.*28C>A
ENST00000615910.4:c.976C>A
ENST00000617185.4:c.*116C>A
ENST00000618944.4:c.*116C>A
ENST00000619186.4:c.532C>A
ENST00000619485.4:c.892C>A
ENST00000620739.4:c.892C>A
ENST00000622645.4:c.*116C>A
ENST00000635293.1:c.892C>A
NM_000546.5:c.1009C>A
NM_001126112.2:c.1009C>A
NM_001126113.2:c.*28C>A
NM_001126114.2:c.*116C>A
NM_001126115.1:c.613C>A
NM_001126116.1:c.*116C>A
NM_001126117.1:c.*28C>A
NM_001126118.1:c.892C>A
NM_001276695.1:c.*28C>A
NM_001276696.1:c.*116C>A
NM_001276697.1:c.532C>A
NM_001276698.1:c.*116C>A
NM_001276699.1:c.*28C>A
NM_001276760.1:c.892C>A
NM_001276761.1:c.892C>A
NM_001276695.2:c.*28C>A
NM_001276696.2:c.*116C>A
NM_001276697.2:c.532C>A
NM_001276698.2:c.*116C>A
NM_001276699.2:c.*28C>A
NM_001276760.2:c.892C>A
NM_000546.6:c.1009C>A
NM_001126112.3:c.1009C>A
NM_001126113.3:c.*28C>A
NM_001126114.3:c.*116C>A
NM_001126115.2:c.613C>A
NM_001126116.2:c.*116C>A
NM_001126117.2:c.*28C>A
NM_001126118.2:c.892C>A
NM_001276695.3:c.*28C>A
NM_001276696.3:c.*116C>A
NM_001276697.3:c.532C>A
NM_001276698.3:c.*116C>A
NM_001276699.3:c.*28C>A
NM_001276760.3:c.892C>A
NM_001276761.3:c.892C>A
More

Likely Pathogenic

Met criteria codes 6
PS4_Supporting PM1_Supporting BP4 PM5_Supporting PS3 PM2_Supporting
Not Met criteria codes 10
BA1 BS2 BS4 BS3 BS1 PS1 PS2 PP4 PP1 PP3

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 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
The NM_000546.6:c.1009C>A variant in TP53 is a missense variant predicted to cause substitution of arginine by serine at amino acid 337 (p.Arg337Ser). This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). Two missense variants (p.Arg337Pro, p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). Computational predictor scores (BayesDel = 0.154096; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -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). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, BP4, PM1_Supporting, PM2_Supporting, PM5_Supporting, PS4_Supporting. (Bayesian Points: 7; VCEP specifications version 2.3)
Met criteria codes
PS4_Supporting
This variant has been reported in 2 unrelated probands meeting Revised Chompret criteria. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMIDs, ClinVar SCVs, Internal lab contributors).
PM1_Supporting
This variant has 4 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting).
BP4
Computational predictor scores (BayesDel = 0.154096; Align GVGD Class C35) are below the recommended thresholds (BayesDel < 0.16 and > -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).
PM5_Supporting
Two missense variants (p.Arg337Pro, p.Arg337Leu) in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting).
PS3
In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965).
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
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
BS3
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
PS1
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
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
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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