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.1135C>A (p.Arg379Ser)

CA000042

186762 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: ec12077e-ef5b-47b0-9426-2498d4b97853
Approved on: 2025-01-16
Published on: 2025-01-16

HGVS expressions

NM_000546.6:c.1135C>A
NM_000546.6(TP53):c.1135C>A (p.Arg379Ser)
NC_000017.11:g.7669656G>T
CM000679.2:g.7669656G>T
NC_000017.10:g.7572974G>T
CM000679.1:g.7572974G>T
NC_000017.9:g.7513699G>T
NG_017013.2:g.22895C>A
ENST00000503591.2:c.1135C>A
ENST00000508793.6:c.1135C>A
ENST00000509690.6:c.739C>A
ENST00000514944.6:c.856C>A
ENST00000604348.6:c.1114C>A
ENST00000269305.9:c.1135C>A
ENST00000269305.8:c.1135C>A
ENST00000359597.8:c.994-3412C>A
ENST00000413465.6:c.782+4525C>A
ENST00000420246.6:c.*242C>A
ENST00000445888.6:c.1135C>A
ENST00000455263.6:c.*154C>A
ENST00000504290.5:c.*154C>A
ENST00000504937.5:c.739C>A
ENST00000510385.5:c.*242C>A
ENST00000576024.1:c.88C>A
ENST00000610292.4:c.1018C>A
ENST00000610538.4:c.*154C>A
ENST00000610623.4:c.*154C>A
ENST00000615910.4:c.1102C>A
ENST00000617185.4:c.*242C>A
ENST00000618944.4:c.*242C>A
ENST00000619186.4:c.658C>A
ENST00000619485.4:c.1018C>A
ENST00000620739.4:c.1018C>A
ENST00000622645.4:c.*242C>A
ENST00000635293.1:c.983+953C>A
NM_000546.5:c.1135C>A
NM_001126112.2:c.1135C>A
NM_001126113.2:c.*154C>A
NM_001126114.2:c.*242C>A
NM_001126115.1:c.739C>A
NM_001126116.1:c.*242C>A
NM_001126117.1:c.*154C>A
NM_001126118.1:c.1018C>A
NM_001276695.1:c.*154C>A
NM_001276696.1:c.*242C>A
NM_001276697.1:c.658C>A
NM_001276698.1:c.*242C>A
NM_001276699.1:c.*154C>A
NM_001276760.1:c.1018C>A
NM_001276761.1:c.1018C>A
NM_001276695.2:c.*154C>A
NM_001276696.2:c.*242C>A
NM_001276697.2:c.658C>A
NM_001276698.2:c.*242C>A
NM_001276699.2:c.*154C>A
NM_001276760.2:c.1018C>A
NM_001276761.2:c.1018C>A
NM_001126112.3:c.1135C>A
NM_001126113.3:c.*154C>A
NM_001126114.3:c.*242C>A
NM_001126115.2:c.739C>A
NM_001126116.2:c.*242C>A
NM_001126117.2:c.*154C>A
NM_001126118.2:c.1018C>A
NM_001276695.3:c.*154C>A
NM_001276696.3:c.*242C>A
NM_001276697.3:c.658C>A
NM_001276698.3:c.*242C>A
NM_001276699.3:c.*154C>A
NM_001276760.3:c.1018C>A
NM_001276761.3:c.1018C>A
More

Likely Benign

Met criteria codes 4
PS4_Supporting BS2 BP4 PM2_Supporting
Not Met criteria codes 12
BA1 BS4 BS3 BS1 PS1 PS2 PS3 PP4 PP1 PP3 PM5 PM1

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.1135C>A variant in TP53 is a missense variant predicted to cause substitution of argine by serine at amino acid 379 (p.Arg379Ser). 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 contributor: Invitae). This variant has been reported in 1 proband meeting Revised Chompret criteria and is reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: Invitae, GeneDx). This variant has an allele frequency of 0.000005932 (7/1179994 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). Computational predictor scores (BayesDel = -0.1497; 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: BS2, PS4_Supporting, PM2_Supporting, BS4_Moderate. (Bayesian Points: -4; VCEP specifications version 2.1; 1/16/2025)
Met criteria codes
PS4_Supporting
This variant has been reported in 1 proband meeting Revised Chompret criteria and is reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total point meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal lab contributors: Invitae, GeneDx).
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 contributor: Invitae).
BP4
BP4_MODERATE. Computational predictor scores (BayesDel = -0.1497; 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 0.000005932 (7/1179994 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).
Not Met criteria codes
BA1
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
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 30224644).
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
PS3
In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 30224644).
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
PM5
3 different missense variants (p.Arg379His, p.Arg379Leu, p.Arg379Cys) in the same codon have been reported. 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).
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).
Curation History
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