Variant: NM_000546.5(TP53):c.353C>T (p.Thr118Ile)

CA16620635

419837 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome 1

Inheritance Mode: Autosomal dominant inheritance

UUID: fc7cc0ba-f84e-46c8-acb3-ef170d24b394

Approved on: 2021-08-03

Published on: 2021-09-24

HGVS expressions

NM_000546.5:c.353C>T
NM_000546.5(TP53):c.353C>T (p.Thr118Ile)
NC_000017.11:g.7676016G>A
CM000679.2:g.7676016G>A
NC_000017.10:g.7579334G>A
CM000679.1:g.7579334G>A
NC_000017.9:g.7520059G>A
NG_017013.2:g.16535C>T
ENST00000269305.9:c.353C>T
ENST00000269305.8:c.353C>T
ENST00000359597.8:n.353C>T
ENST00000413465.6:n.353C>T
ENST00000420246.6:c.353C>T
ENST00000445888.6:c.353C>T
ENST00000455263.6:c.353C>T
ENST00000503591.1:c.353C>T
ENST00000505014.5:n.609C>T
ENST00000508793.5:c.353C>T
ENST00000509690.5:c.-21-780C>T
ENST00000514944.5:c.96+366C>T
ENST00000604348.5:c.353C>T
ENST00000610292.4:c.236C>T
ENST00000610538.4:c.236C>T
ENST00000615910.4:n.340+9C>T
ENST00000617185.4:c.353C>T
ENST00000619485.4:c.236C>T
ENST00000620739.4:c.236C>T
ENST00000622645.4:c.236C>T
ENST00000635293.1:c.236C>T
NM_001126112.2:c.353C>T
NM_001126113.2:c.353C>T
NM_001126114.2:c.353C>T
NM_001126118.1:c.236C>T
NM_001276695.1:c.236C>T
NM_001276696.1:c.236C>T
NM_001276760.1:c.236C>T
NM_001276761.1:c.236C>T
NM_001276695.2:c.236C>T
NM_001276696.2:c.236C>T
NM_001276760.2:c.236C>T
NM_001276761.2:c.236C>T
NM_000546.6:c.353C>T
NM_001126112.3:c.353C>T
NM_001126113.3:c.353C>T
NM_001126114.3:c.353C>T
NM_001126118.2:c.236C>T
NM_001276695.3:c.236C>T
NM_001276696.3:c.236C>T
NM_001276760.3:c.236C>T
NM_001276761.3:c.236C>T

Uncertain Significance

• Met criteria codes: BS2_Supporting PP3_Moderate PM2_Supporting BS3

• Not Met criteria codes: BP2 BP4 PM6 PM1 PM5 PS2 PS3 PS1 BA1 PP1 BS4 BS1

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 65 (PP3_Moderate). This variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting; Ambry Genetics). Transactivation assays show retained 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, the clinical significance of TP53 c.353C>T (p.Thr118Ile) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, BS2_Supporting, BS3

Met criteria codes

• BS2_Supporting: 2 females cancer free at age 60 in Ambry internal data
• PP3_Moderate: AlignGVGD C65, BayesDel 0.34663
• PM2_Supporting: Absent in gnomAD v2.1.1 (non-cancer)
• BS3: Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF

Not Met criteria codes

• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: AlignGVGD C65, BayesDel 0.34663
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No hotspot, not in cancerhotspots.org
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Absent in gnomAD v2.1.1 (non-cancer)
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: Absent in gnomAD v2.1.1 (non-cancer)