Variant: NM_000546.5(TP53):c.455C>T (p.Pro152Leu)

CA000204

142766 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 6bf64717-7983-4329-bddb-4b28f0690106

Approved on: 2019-08-28

Published on: 2020-01-24

HGVS expressions

NM_000546.5:c.455C>T
NM_000546.5(TP53):c.455C>T (p.Pro152Leu)
NC_000017.11:g.7675157G>A
CM000679.2:g.7675157G>A
NC_000017.10:g.7578475G>A
CM000679.1:g.7578475G>A
NC_000017.9:g.7519200G>A
NG_017013.2:g.17394C>T
ENST00000503591.2:c.455C>T
ENST00000508793.6:c.455C>T
ENST00000509690.6:c.59C>T
ENST00000514944.6:c.176C>T
ENST00000604348.6:c.434C>T
ENST00000269305.9:c.455C>T
ENST00000269305.8:c.455C>T
ENST00000359597.8:c.455C>T
ENST00000413465.6:c.455C>T
ENST00000420246.6:c.455C>T
ENST00000445888.6:c.455C>T
ENST00000455263.6:c.455C>T
ENST00000504290.5:c.59C>T
ENST00000504937.5:c.59C>T
ENST00000505014.5:n.711C>T
ENST00000508793.5:c.455C>T
ENST00000509690.5:c.59C>T
ENST00000510385.5:c.59C>T
ENST00000514944.5:c.176C>T
ENST00000610292.4:c.338C>T
ENST00000610538.4:c.338C>T
ENST00000610623.4:c.-23C>T
ENST00000615910.4:c.422C>T
ENST00000617185.4:c.455C>T
ENST00000618944.4:c.-23C>T
ENST00000619186.4:c.-23C>T
ENST00000619485.4:c.338C>T
ENST00000620739.4:c.338C>T
ENST00000622645.4:c.338C>T
ENST00000635293.1:c.338C>T
NM_001126112.2:c.455C>T
NM_001126113.2:c.455C>T
NM_001126114.2:c.455C>T
NM_001126115.1:c.59C>T
NM_001126116.1:c.59C>T
NM_001126117.1:c.59C>T
NM_001126118.1:c.338C>T
NM_001276695.1:c.338C>T
NM_001276696.1:c.338C>T
NM_001276697.1:c.-23C>T
NM_001276698.1:c.-23C>T
NM_001276699.1:c.-23C>T
NM_001276760.1:c.338C>T
NM_001276761.1:c.338C>T
NM_001276695.2:c.338C>T
NM_001276696.2:c.338C>T
NM_001276697.2:c.-23C>T
NM_001276698.2:c.-23C>T
NM_001276699.2:c.-23C>T
NM_001276760.2:c.338C>T
NM_001276761.2:c.338C>T
NM_000546.6:c.455C>T
NM_001126112.3:c.455C>T
NM_001126113.3:c.455C>T
NM_001126114.3:c.455C>T
NM_001126115.2:c.59C>T
NM_001126116.2:c.59C>T
NM_001126117.2:c.59C>T
NM_001126118.2:c.338C>T
NM_001276695.3:c.338C>T
NM_001276696.3:c.338C>T
NM_001276697.3:c.-23C>T
NM_001276698.3:c.-23C>T
NM_001276699.3:c.-23C>T
NM_001276760.3:c.338C>T
NM_001276761.3:c.338C>T

Pathogenic

• Met criteria codes: PP3_Moderate PP1 PS3 PS4 PM1

• Not Met criteria codes: BP4

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). The variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). 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 8 probands meeting Chompret criteria (PS4; PMID: 25584008, 10486318, 17308077, 15654279, 26014290). Additionally, this variant was found to co-segregate with disease in multiple affected family members, with at least 3 meioses observed (PP1; PMID: 10486318). In summary, TP53 c.455C>T; p.Pro152Leu meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3_Moderate, PM1, PS3, PS4, PP1.

Met criteria codes

• PP3_Moderate: AGVGD score is C65 and BayesDel score is >0.16
• PP1: Varley, et al 1999 family with 3 meioses. Proband = 3 points
• PS3: Transactivation assay classification is non-functional; yeast colony assay show decreased growth suppression.
• PS4: 8 probands meeting Chompret criteria = 4 points
• PM1: 28 observations in cancerhotspots.org

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline