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_000546.5(TP53):c.541C>A (p.Arg181Ser)

CA10580940

230764 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: dc88e22c-bbbf-4aeb-9c2a-0e3babeaaeed
Approved on: 2025-03-04
Published on: 2025-06-23

HGVS expressions

NM_000546.5:c.541C>A
NM_000546.5(TP53):c.541C>A (p.Arg181Ser)
NC_000017.11:g.7675071G>T
CM000679.2:g.7675071G>T
NC_000017.10:g.7578389G>T
CM000679.1:g.7578389G>T
NC_000017.9:g.7519114G>T
NG_017013.2:g.17480C>A
ENST00000503591.2:c.541C>A
ENST00000508793.6:c.541C>A
ENST00000509690.6:c.145C>A
ENST00000514944.6:c.262C>A
ENST00000604348.6:c.520C>A
ENST00000269305.9:c.541C>A
ENST00000269305.8:c.541C>A
ENST00000359597.8:c.541C>A
ENST00000413465.6:c.541C>A
ENST00000420246.6:c.541C>A
ENST00000445888.6:c.541C>A
ENST00000455263.6:c.541C>A
ENST00000504290.5:c.145C>A
ENST00000504937.5:c.145C>A
ENST00000505014.5:n.797C>A
ENST00000509690.5:c.145C>A
ENST00000510385.5:c.145C>A
ENST00000514944.5:c.262C>A
ENST00000574684.1:n.49C>A
ENST00000610292.4:c.424C>A
ENST00000610538.4:c.424C>A
ENST00000610623.4:c.64C>A
ENST00000615910.4:c.508C>A
ENST00000617185.4:c.541C>A
ENST00000618944.4:c.64C>A
ENST00000619186.4:c.64C>A
ENST00000619485.4:c.424C>A
ENST00000620739.4:c.424C>A
ENST00000622645.4:c.424C>A
ENST00000635293.1:c.424C>A
NM_001126112.2:c.541C>A
NM_001126113.2:c.541C>A
NM_001126114.2:c.541C>A
NM_001126115.1:c.145C>A
NM_001126116.1:c.145C>A
NM_001126117.1:c.145C>A
NM_001126118.1:c.424C>A
NM_001276695.1:c.424C>A
NM_001276696.1:c.424C>A
NM_001276697.1:c.64C>A
NM_001276698.1:c.64C>A
NM_001276699.1:c.64C>A
NM_001276760.1:c.424C>A
NM_001276761.1:c.424C>A
NM_001276695.2:c.424C>A
NM_001276696.2:c.424C>A
NM_001276697.2:c.64C>A
NM_001276698.2:c.64C>A
NM_001276699.2:c.64C>A
NM_001276760.2:c.424C>A
NM_001276761.2:c.424C>A
NM_000546.6:c.541C>A
NM_001126112.3:c.541C>A
NM_001126113.3:c.541C>A
NM_001126114.3:c.541C>A
NM_001126115.2:c.145C>A
NM_001126116.2:c.145C>A
NM_001126117.2:c.145C>A
NM_001126118.2:c.424C>A
NM_001276695.3:c.424C>A
NM_001276696.3:c.424C>A
NM_001276697.3:c.64C>A
NM_001276698.3:c.64C>A
NM_001276699.3:c.64C>A
NM_001276760.3:c.424C>A
NM_001276761.3:c.424C>A
More

Uncertain Significance

Met criteria codes 4
PM2_Supporting BS3_Supporting BS2_Supporting PP3_Moderate
Not Met criteria codes 11
BA1 BS4 BS1 BP4 PS4 PS1 PS2 PS3 PP1 PM1 PM6

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.541C>A variant in TP53 is a missense variant predicted to cause substitution of arginine by serine at amino acid 181 (p.Arg181Ser). This variant has been observed in 3 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_Supporting; Ambry SCV000274425.4). This variant received a total of 0.5 points across 1 family meeting Chompret criteria and does not meet criteria for PS4 (PS4 not met; IARC database). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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 (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.204; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be 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_supporting, PM2_supporting, BS3_supporting, PP3_moderate (Bayesian Points: 1; VCEP specifications version 2.3).
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
BS3_Supporting
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 (BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).
BS2_Supporting
This variant has been observed in 3 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_Supporting; Ambry SCV000274425.4).
PP3_Moderate
Computational predictor scores (BayesDel = 0.204; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate).
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
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
PS4
This variant received a total of 0.5 points across 1 family meeting Chompret criteria and does not meet criteria for PS4 (PS4 not met; IARC database).
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
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
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).
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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