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 label mismatch: TP53 vs undefined
  • 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.1009C>T (p.Arg337Cys)

CA000010

142536 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4424bcab-bb1a-4d11-bac2-48862c2e987b
Approved on: 2025-05-07
Published on: 2025-07-18

HGVS expressions

NM_000546.6:c.1009C>T
NM_000546.6(TP53):c.1009C>T (p.Arg337Cys)
NC_000017.11:g.7670700G>A
CM000679.2:g.7670700G>A
NC_000017.10:g.7574018G>A
CM000679.1:g.7574018G>A
NC_000017.9:g.7514743G>A
NG_017013.2:g.21851C>T
ENST00000503591.2:c.1009C>T
ENST00000508793.6:c.1009C>T
ENST00000509690.6:c.613C>T
ENST00000514944.6:c.730C>T
ENST00000604348.6:c.988C>T
ENST00000269305.9:c.1009C>T
ENST00000269305.8:c.1009C>T
ENST00000359597.8:c.993+2835C>T
ENST00000413465.6:c.782+3481C>T
ENST00000420246.6:c.*116C>T
ENST00000445888.6:c.1009C>T
ENST00000455263.6:c.*28C>T
ENST00000504290.5:c.*28C>T
ENST00000504937.5:c.613C>T
ENST00000510385.5:c.*116C>T
ENST00000576024.1:c.54-1010C>T
ENST00000610292.4:c.892C>T
ENST00000610538.4:c.*28C>T
ENST00000610623.4:c.*28C>T
ENST00000615910.4:c.976C>T
ENST00000617185.4:c.*116C>T
ENST00000618944.4:c.*116C>T
ENST00000619186.4:c.532C>T
ENST00000619485.4:c.892C>T
ENST00000620739.4:c.892C>T
ENST00000622645.4:c.*116C>T
ENST00000635293.1:c.892C>T
NM_000546.5:c.1009C>T
NM_001126112.2:c.1009C>T
NM_001126113.2:c.*28C>T
NM_001126114.2:c.*116C>T
NM_001126115.1:c.613C>T
NM_001126116.1:c.*116C>T
NM_001126117.1:c.*28C>T
NM_001126118.1:c.892C>T
NM_001276695.1:c.*28C>T
NM_001276696.1:c.*116C>T
NM_001276697.1:c.532C>T
NM_001276698.1:c.*116C>T
NM_001276699.1:c.*28C>T
NM_001276760.1:c.892C>T
NM_001276761.1:c.892C>T
NM_001276695.2:c.*28C>T
NM_001276696.2:c.*116C>T
NM_001276697.2:c.532C>T
NM_001276698.2:c.*116C>T
NM_001276699.2:c.*28C>T
NM_001276760.2:c.892C>T
NM_001276761.2:c.892C>T
NM_001126112.3:c.1009C>T
NM_001126113.3:c.*28C>T
NM_001126114.3:c.*116C>T
NM_001126115.2:c.613C>T
NM_001126116.2:c.*116C>T
NM_001126117.2:c.*28C>T
NM_001126118.2:c.892C>T
NM_001276695.3:c.*28C>T
NM_001276696.3:c.*116C>T
NM_001276697.3:c.532C>T
NM_001276698.3:c.*116C>T
NM_001276699.3:c.*28C>T
NM_001276760.3:c.892C>T
NM_001276761.3:c.892C>T
More

Pathogenic

Met criteria codes 8
PM1 PS4 PS2 PS3 PM2_Supporting PP3 PP4_Moderate PM5_Supporting
Not Met criteria codes 4
BS3 BS1 BP4 PP1

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(TP53):c.1009C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 337 (p.Arg337Cys). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 5 phenotype points (PS2; PMID: 18511570, Internal lab contributors). This variant has been reported in 10 unrelated families meeting Revised Chompret; 1 family meeting classic; and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 1353190, 9452042; Internal lab contributors). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, 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 36 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 (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.316468; Align GVGD = Class C45) 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). Three missense variants (p.Arg337Ser, 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). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PM1, PS4, PP3, PP4_Moderate, PM2_Supporting, PM5_Supporting, PS2. (Bayesian Points: 19; VCEP specifications version 2.3)
Met criteria codes
PM1
This variant has 36 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 (≥ 10 somatic occurrences, PMID: 30311369) (PM1).
PS4
This variant has been reported in 10 unrelated families meeting Revised Chompret; 1 family meeting classic; and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 6.5 total points meeting the TP53 VCEP phenotype scoring criteria of 4-7.5 points. (PS4; PMIDs: 1353190, 9452042; Internal lab contributors).
PS2
This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer and as a de novo occurrence with unconfirmed parental relationships in 1 individual with a moderately LFS-associated cancer totaling 5 phenotype points (PS2; PMID: 18511570, Internal lab contributors).
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).
PP3
Computational predictor scores (BayesDel = 0.316468; Align GVGD = Class C45) 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).
PP4_Moderate
At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors).
PM5_Supporting
Three missense variants (p.Arg337Ser, 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).
Not Met criteria codes
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
BP4
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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