Variant: NM_000546.5(TP53):c.11C>T (p.Pro4Leu)

CA10583686

237941 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: 410f531a-d916-4dbc-9751-ea42adb439f2

Approved on: 2021-08-04

Published on: 2021-09-24

HGVS expressions

NM_000546.5:c.11C>T
NM_000546.5(TP53):c.11C>T (p.Pro4Leu)
ENST00000269305.9:c.11C>T
ENST00000269305.8:c.11C>T
ENST00000359597.8:n.11C>T
ENST00000413465.6:n.11C>T
ENST00000420246.6:c.11C>T
ENST00000445888.6:c.11C>T
ENST00000455263.6:c.11C>T
ENST00000503591.1:c.11C>T
ENST00000505014.5:n.150C>T
ENST00000508793.5:c.11C>T
ENST00000509690.5:c.-21-1348C>T
ENST00000514944.5:c.11C>T
ENST00000604348.5:c.11C>T
ENST00000610292.4:c.-224C>T
ENST00000610538.4:c.-107C>T
ENST00000615910.4:n.11C>T
ENST00000617185.4:c.11C>T
ENST00000619485.4:c.-107C>T
ENST00000620739.4:c.-107C>T
ENST00000622645.4:c.-107C>T
ENST00000635293.1:c.-107C>T
NM_001126112.2:c.11C>T
NM_001126113.2:c.11C>T
NM_001126114.2:c.11C>T
NM_001126118.1:c.-224C>T
NM_001276695.1:c.-107C>T
NM_001276696.1:c.-107C>T
NM_001276760.1:c.-107C>T
NM_001276761.1:c.-107C>T
NM_001276695.2:c.-107C>T
NM_001276696.2:c.-107C>T
NM_001276760.2:c.-107C>T
NM_001276761.2:c.-107C>T
NM_000546.6:c.11C>T
NM_001126112.3:c.11C>T
NM_001126113.3:c.11C>T
NM_001126114.3:c.11C>T
NM_001126118.2:c.-224C>T
NM_001276695.3:c.-107C>T
NM_001276696.3:c.-107C>T
NM_001276760.3:c.-107C>T
NM_001276761.3:c.-107C>T
NC_000017.11:g.7676584G>A
CM000679.2:g.7676584G>A
NC_000017.10:g.7579902G>A
CM000679.1:g.7579902G>A
NC_000017.9:g.7520627G>A
NG_017013.2:g.15967C>T

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BP4 BS3 PM2_Supporting

• Not Met criteria codes: BA1 BP7 BP2 BS2 BS4 BS1 PVS1 PP1 PP3 PM1 PM5 PS4 PS3 PS1

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). Transactivation assays show [retained/supertransactivation] 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). In summary, TP53 c.11C>T (p.Pro4Leu) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, BP4, BS3.

Met criteria codes

• BP4: Align-GVGD is C0 and BayesDel is 0.0629
• BS3: Functional (Kato, 94.3%% mean transactivation activity (>75%)) noDNE+noLOF (Giacomelli, p53WTNutlin3 Z-score -0.367(< 0.61) and Etoposide Z-score 0.356(> -0.21 ))
• PM2_Supporting: absent from population databases

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: 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
• BS2: Observed in 1 60+ year old cancer free female from internal laboratory data
• BS4: 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
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Align-GVGD is C0 and BayesDel is 0.0629
• PM1: Not met (Not selected codon (175, 248, 273, 248, 245, 282, 249) or seen in cancerhotspots.org)
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: Functional (Kato, 94.3%% mean transactivation activity (>75%)) noDNE+noLOF (Giacomelli, p53WTNutlin3 Z-score -0.367(< 0.61) and Etoposide Z-score 0.356(> -0.21 ))
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline