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.818G>A (p.Arg273His)

CA000434

12366 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: 8d32df42-16ac-41f2-9bf1-e2b9ce206190

HGVS expressions

NM_000546.5:c.818G>A
NM_000546.5(TP53):c.818G>A (p.Arg273His)
NC_000017.11:g.7673802C>T
CM000679.2:g.7673802C>T
NC_000017.10:g.7577120C>T
CM000679.1:g.7577120C>T
NC_000017.9:g.7517845C>T
NG_017013.2:g.18749G>A
NM_001126112.2:c.818G>A
NM_001126113.2:c.818G>A
NM_001126114.2:c.818G>A
NM_001126115.1:c.422G>A
NM_001126116.1:c.422G>A
NM_001126117.1:c.422G>A
NM_001126118.1:c.701G>A
NM_001276695.1:c.701G>A
NM_001276696.1:c.701G>A
NM_001276697.1:c.341G>A
NM_001276698.1:c.341G>A
NM_001276699.1:c.341G>A
NM_001276760.1:c.701G>A
NM_001276761.1:c.701G>A
ENST00000269305.8:c.818G>A
ENST00000359597.8:n.818G>A
ENST00000413465.6:n.782+379G>A
ENST00000420246.6:c.818G>A
ENST00000445888.6:c.818G>A
ENST00000455263.6:c.818G>A
ENST00000504290.5:c.422G>A
ENST00000504937.5:c.422G>A
ENST00000509690.5:c.422G>A
ENST00000510385.5:c.422G>A
ENST00000610292.4:c.701G>A
ENST00000610538.4:c.701G>A
ENST00000610623.4:c.341G>A
ENST00000615910.4:n.785G>A
ENST00000617185.4:c.818G>A
ENST00000618944.4:c.341G>A
ENST00000619186.4:c.341G>A
ENST00000619485.4:c.701G>A
ENST00000620739.4:c.701G>A
ENST00000622645.4:c.701G>A
ENST00000635293.1:c.701G>A

Pathogenic

Met criteria codes 5
PS3 PS2 PS4 PP3 PM1
Not Met criteria codes 2
BA1 BS1

Evidence Links 9

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting Classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PS4; PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, there is a de novo observation of a proband with breast cancer at age 29 with parental confirmation (PS2; PMID: 12672316). In summary, TP53 c.818G>A; p.Arg273His meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2.
Met criteria codes
PS3
Non-functional variant in T-A assays; evidence of DNE & LOF in Giacomelli, et al data

PS2
Clinical data from patient diagnosed with early onset breast cancer, renal cell carcinoma and a liposarcoma submitted by EP member.

PS4
Counted 4 probands as Chrompret and 2 as Classic with a total point score of 4. Many additional probands in literature that were not counted due to maxing out the number of points for this code.

PP3
BayesDel and AGVGD are concordant
PM1
Codon 273 is a hotspot
Not Met criteria codes
BA1
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
Approved on: 2019-08-28
Published on: 2020-01-24
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