The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Criteria Specification: CSpec Registry PDF

Variant: NM_000546.5(TP53):c.743G>A (p.Arg248Gln)

CA000387

12356 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: cf887752-8539-4177-a74d-dc5c8f8a36ed

HGVS expressions

NM_000546.5:c.743G>A
NM_000546.5(TP53):c.743G>A (p.Arg248Gln)
NC_000017.11:g.7674220C>T
CM000679.2:g.7674220C>T
NC_000017.10:g.7577538C>T
CM000679.1:g.7577538C>T
NC_000017.9:g.7518263C>T
NG_017013.2:g.18331G>A
NM_001126112.2:c.743G>A
NM_001126113.2:c.743G>A
NM_001126114.2:c.743G>A
NM_001126115.1:c.347G>A
NM_001126116.1:c.347G>A
NM_001126117.1:c.347G>A
NM_001126118.1:c.626G>A
NM_001276695.1:c.626G>A
NM_001276696.1:c.626G>A
NM_001276697.1:c.266G>A
NM_001276698.1:c.266G>A
NM_001276699.1:c.266G>A
NM_001276760.1:c.626G>A
NM_001276761.1:c.626G>A
ENST00000269305.8:c.743G>A
ENST00000359597.8:n.743G>A
ENST00000413465.6:n.743G>A
ENST00000420246.6:c.743G>A
ENST00000445888.6:c.743G>A
ENST00000455263.6:c.743G>A
ENST00000504290.5:c.347G>A
ENST00000504937.5:c.347G>A
ENST00000509690.5:c.347G>A
ENST00000510385.5:c.347G>A
ENST00000514944.5:c.464G>A
ENST00000610292.4:c.626G>A
ENST00000610538.4:c.626G>A
ENST00000610623.4:c.266G>A
ENST00000615910.4:n.710G>A
ENST00000617185.4:c.743G>A
ENST00000618944.4:c.266G>A
ENST00000619186.4:c.266G>A
ENST00000619485.4:c.626G>A
ENST00000620739.4:c.626G>A
ENST00000622645.4:c.626G>A
ENST00000635293.1:c.626G>A

Pathogenic

Met criteria codes 5
PM1 PS3 PS2 PS4 PP3
Not Met criteria codes 4
BA1 BS1 BP4 PP1

Expert Panel

Evidence Links 5

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 3 probands meeting Classic Li-Fraumeni syndrome and 2 probands meeting Chompret criteria (PS4; PMID: 1565143, 9242456, 15381368, 7887414). There is a de novo observation of a proband with adrenocortical carcinoma with parental confirmation (PS2; PMID: 15381368). In summary, TP53 c.743G>A; p.Arg248Gln 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
PM1
Codon 248 is a hotspot
PS3
Low function on T-A assay and p53 mouse models displaying gain of function in tumorigenesis.

PS2
2 pts assigned for Bendig, et al 2004 case

PS4
3 probands meeting Classic criteria and 2 probands meeting Chrompret criteria. 4 total points.

PP3
BayesDel & AGVGD concordant
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
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Only 6 meiosis among several families at this point.

Approved on: 2019-08-28
Published on: 2020-01-24
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