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]
  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.541C>A (p.Arg181Ser)

CA10580940

230764 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Link to MONDO
UUID: dc88e22c-bbbf-4aeb-9c2a-0e3babeaaeed
Approved on: 2020-08-11
Published on: 2020-08-14

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
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
ENST00000269305.8:c.541C>A
ENST00000359597.8:n.541C>A
ENST00000413465.6:n.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:n.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
More

Uncertain Significance

Met criteria codes 4
BS3_Supporting PP3_Moderate BS2_Supporting PM2_Supporting
Not Met criteria codes 13
BA1 PS3 PS2 PS1 PS4 PP1 PM6 PM5 PM1 BS1 BS4 BP4 BP2

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant has a BayesDel score >0.16 and Align GVGD (Zebrafish) is Class C65 (PP3_Moderate). This variant is absent in the gnomAD cohort (PM2; http://gnomad.broadinstitute.org). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). Transactivation assays show partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.541C>A (p.Arg181Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3_Moderate; BS3_Supporting; PM2_Supporting; BS2_Supporting.
Met criteria codes
BS3_Supporting
Arg181Ser is partially functional in Kato data from IARC. Giacomelli et al is 0.19 ( less than 0.61 cut off), and Kotler data is -2.3 RFS score. (PMID: 12826609, 30224644 ).
Score of 0.19 PubMed:30224644
Partially functional in Kato PubMed:12826609
-2.3 RFS in Kotler PubMed:29979965
PP3_Moderate
This variant has a BayesDel score 0.204 (>0.16) and Align GVGD (Zebrafish) is Class C65 (PP3_Moderate).
BS2_Supporting
Not in FLOSSIES. Ambry labs has 3 cases that are cancer free until age 60 (SCV000274425.4).
PM2_Supporting
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org).
Not Met criteria codes
BA1
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
PS2
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
PS4
One family listed in IARC database: Proband breast@27; father glioblastoma@70; pat cousin breast@40; pat cousin breast@40; pat cousin colon@67 – meets Chompret 0.5 points. No other reports in literature or internal data of clinical labs. Not enough to meet.
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not a hotspot, not in cancerhotspots.org
BS1
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
BP4
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
Curation History
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