Variant: NM_000546.5(TP53):c.877G>T (p.Gly293Trp)

CA000470

127826 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: fcf81c41-2ef5-4155-8668-25fc599a1d42

Approved on: 2020-08-11

Published on: 2020-08-14

HGVS expressions

NM_000546.5:c.877G>T
NM_000546.5(TP53):c.877G>T (p.Gly293Trp)
NC_000017.11:g.7673743C>A
CM000679.2:g.7673743C>A
NC_000017.10:g.7577061C>A
CM000679.1:g.7577061C>A
NC_000017.9:g.7517786C>A
NG_017013.2:g.18808G>T
ENST00000503591.2:c.877G>T
ENST00000508793.6:c.877G>T
ENST00000509690.6:c.481G>T
ENST00000514944.6:c.598G>T
ENST00000604348.6:c.856G>T
ENST00000269305.9:c.877G>T
ENST00000269305.8:c.877G>T
ENST00000359597.8:c.877G>T
ENST00000413465.6:c.782+438G>T
ENST00000420246.6:c.877G>T
ENST00000445888.6:c.877G>T
ENST00000455263.6:c.877G>T
ENST00000504290.5:c.481G>T
ENST00000504937.5:c.481G>T
ENST00000509690.5:c.481G>T
ENST00000510385.5:c.481G>T
ENST00000610292.4:c.760G>T
ENST00000610538.4:c.760G>T
ENST00000610623.4:c.400G>T
ENST00000615910.4:c.844G>T
ENST00000617185.4:c.877G>T
ENST00000618944.4:c.400G>T
ENST00000619186.4:c.400G>T
ENST00000619485.4:c.760G>T
ENST00000620739.4:c.760G>T
ENST00000622645.4:c.760G>T
ENST00000635293.1:c.760G>T
NM_001126112.2:c.877G>T
NM_001126113.2:c.877G>T
NM_001126114.2:c.877G>T
NM_001126115.1:c.481G>T
NM_001126116.1:c.481G>T
NM_001126117.1:c.481G>T
NM_001126118.1:c.760G>T
NM_001276695.1:c.760G>T
NM_001276696.1:c.760G>T
NM_001276697.1:c.400G>T
NM_001276698.1:c.400G>T
NM_001276699.1:c.400G>T
NM_001276760.1:c.760G>T
NM_001276761.1:c.760G>T
NM_001276695.2:c.760G>T
NM_001276696.2:c.760G>T
NM_001276697.2:c.400G>T
NM_001276698.2:c.400G>T
NM_001276699.2:c.400G>T
NM_001276760.2:c.760G>T
NM_001276761.2:c.760G>T
NM_000546.6:c.877G>T
NM_001126112.3:c.877G>T
NM_001126113.3:c.877G>T
NM_001126114.3:c.877G>T
NM_001126115.2:c.481G>T
NM_001126116.2:c.481G>T
NM_001126117.2:c.481G>T
NM_001126118.2:c.760G>T
NM_001276695.3:c.760G>T
NM_001276696.3:c.760G>T
NM_001276697.3:c.400G>T
NM_001276698.3:c.400G>T
NM_001276699.3:c.400G>T
NM_001276760.3:c.760G>T
NM_001276761.3:c.760G>T

Likely Benign

• Met criteria codes: BS3 BS2_Supporting

• Not Met criteria codes: BS1 BP4 BP2 PM1 PM5 PM2 PS1 PS3 PS4 PP3 BA1

Expert Panel

TP53 VCEP

Criteria Specification Information

Evidence submitted by expert panel

TP53 VCEP

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). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.877G>T (p.Gly293Trp) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: BS3; BS2_Supporting.

Met criteria codes

• BS3: Transactivation assay in yeast (Kato et al, 2003) shows retained function. No evidence of dominant negative effect (DNE) or loss of function (LOF) (Giacomelli et al, 2018). Additional assays further support the lack of dominant negative activity and retained transcription activity toward 8/8 p53 response elements (Monti et al, 2007, 2011).
• BS2_Supporting: Variant only identified in 1/9884 females in FLOSSIES database. Ambry labs has 4 cases cancer free at age 60 (SCV000187101.5).

Not Met criteria codes

• BP4: Align-GVGD Class C0, suggesting non-pathogenicity, but BayesDel score is 0.2026 (>0.16), suggesting pathogenicity.
• BP2: None reported.
• PM1: Variant is not in one of the six known mutational hot spot codons (175, 245, 248, 249, 273, 282) and not present in cancerhotspots.org
• PM5: One other amino acid change has been reported at this codon (p.G293R; ClinVar ID: 230208), but this change has not been reported as pathogenic at this time.
• PM2: Variant not absent from controls.
• PS1: None reported.
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This germline variant has been detected in 3 cancer patients reported in the literautre: a male with history of Hodgkin's lymphoma, melanoma, and sarcoma (with loss of heterozygosity for the TP53 variant) diagnosed at ages 34, 47, and 60 years, respectively (Mitchell 2013); a 17-year-old female with Neurofibromatosis Type 1 and Grade III glioblastoma which demonstrated loss of heterozygosity of chromosomes 10 and 17 (variant paternally inherited) (Chung 1991); and an individual with breast cancer who otherwise tested negative on a multi-gene panel (Tung 2016). Current information in the literature is insufficient to classify these individuals as meeting LFS diagnostic criteria. This variant has also been identified in 28+ individuals according to internal data from genetic testing laboratories. One case meets Chompret criteria (0.5 points, SCV000149650.14).
• PP3: Align-GVGD Class C0, suggesting non-pathogenicity, but BayesDel score is 0.2026 (>0.16), suggesting pathogenicity.
• BA1: Low allele frequency of 0.000025 in European (non-Finnish) population in gnomAD (non-cancer) and absent from other populations.