Variant: NM_000546.5(TP53):c.869G>A (p.Arg290His)

CA000468

127825 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: de5ede53-7b6d-40ad-8a0e-0b3aa4c7ecd8

HGVS expressions

NM_000546.5:c.869G>A
NM_000546.5(TP53):c.869G>A (p.Arg290His)
NC_000017.11:g.7673751C>T
CM000679.2:g.7673751C>T
NC_000017.10:g.7577069C>T
CM000679.1:g.7577069C>T
NC_000017.9:g.7517794C>T
NG_017013.2:g.18800G>A
NM_001126112.2:c.869G>A
NM_001126113.2:c.869G>A
NM_001126114.2:c.869G>A
NM_001126115.1:c.473G>A
NM_001126116.1:c.473G>A
NM_001126117.1:c.473G>A
NM_001126118.1:c.752G>A
NM_001276695.1:c.752G>A
NM_001276696.1:c.752G>A
NM_001276697.1:c.392G>A
NM_001276698.1:c.392G>A
NM_001276699.1:c.392G>A
NM_001276760.1:c.752G>A
NM_001276761.1:c.752G>A
ENST00000269305.8:c.869G>A
ENST00000359597.8:n.869G>A
ENST00000413465.6:n.782+430G>A
ENST00000420246.6:c.869G>A
ENST00000445888.6:c.869G>A
ENST00000455263.6:c.869G>A
ENST00000504290.5:c.473G>A
ENST00000504937.5:c.473G>A
ENST00000509690.5:c.473G>A
ENST00000510385.5:c.473G>A
ENST00000610292.4:c.752G>A
ENST00000610538.4:c.752G>A
ENST00000610623.4:c.392G>A
ENST00000615910.4:n.836G>A
ENST00000617185.4:c.869G>A
ENST00000618944.4:c.392G>A
ENST00000619186.4:c.392G>A
ENST00000619485.4:c.752G>A
ENST00000620739.4:c.752G>A
ENST00000622645.4:c.752G>A
ENST00000635293.1:c.752G>A

Benign

• Met criteria codes: BS2_Supporting BS3 BS1 BP4

• Not Met criteria codes: PP4

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant has a minor allele frequency of 0.0003583 (0.03%, 9/25,120 alleles) in the European Finnish subpopulation of the gnomAD cohort (BS1). Transactivation assays show super transactivation function 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; PMID: 12826609, 30224644). Additionally, this variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Finally, this variant has been observed in at least 7 60+ year old females without a cancer diagnosis (BS2_Supporting; FLOSSIES database - https://whi.color.com). In summary, TP53 c.869G>A; p.Arg290His meets criteria to be classified as benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS1, BS3, BP4, BS2_Supporting.

Met criteria codes

• BS2_Supporting: Variant observed in 7 individuals from the FLOSSIES data.
• BS3: Kato, et al data classifies as supertrans & variant has no LOF and dominant negative effects according to Giacomelli, et al
• BS1: 0.027% (rounds up to 0.03%) with 7 alleles in the Finnish population
• BP4: BayesDel suggests benign; AGVGD = Class C0

Not Met criteria codes

• PP4: Several probands in the literature meet Chrompret cirteria.

Approved on: 2019-09-16

Published on: 2020-01-24