The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_001126112.2(TP53):c.845G>T (p.Arg282Leu)

CA000456

182938 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
UUID: 8099c951-8c94-4ef5-9f48-ba68e4b64b16
Approved on: 2021-04-12
Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.845G>T
NM_001126112.2(TP53):c.845G>T (p.Arg282Leu)
ENST00000269305.9:c.845G>T
ENST00000269305.8:c.845G>T
ENST00000359597.8:n.845G>T
ENST00000413465.6:n.782+406G>T
ENST00000420246.6:c.845G>T
ENST00000445888.6:c.845G>T
ENST00000455263.6:c.845G>T
ENST00000504290.5:c.449G>T
ENST00000504937.5:c.449G>T
ENST00000509690.5:c.449G>T
ENST00000510385.5:c.449G>T
ENST00000610292.4:c.728G>T
ENST00000610538.4:c.728G>T
ENST00000610623.4:c.368G>T
ENST00000615910.4:n.812G>T
ENST00000617185.4:c.845G>T
ENST00000618944.4:c.368G>T
ENST00000619186.4:c.368G>T
ENST00000619485.4:c.728G>T
ENST00000620739.4:c.728G>T
ENST00000622645.4:c.728G>T
ENST00000635293.1:c.728G>T
NM_000546.5:c.845G>T
NM_001126113.2:c.845G>T
NM_001126114.2:c.845G>T
NM_001126115.1:c.449G>T
NM_001126116.1:c.449G>T
NM_001126117.1:c.449G>T
NM_001126118.1:c.728G>T
NM_001276695.1:c.728G>T
NM_001276696.1:c.728G>T
NM_001276697.1:c.368G>T
NM_001276698.1:c.368G>T
NM_001276699.1:c.368G>T
NM_001276760.1:c.728G>T
NM_001276761.1:c.728G>T
NM_001276695.2:c.728G>T
NM_001276696.2:c.728G>T
NM_001276697.2:c.368G>T
NM_001276698.2:c.368G>T
NM_001276699.2:c.368G>T
NM_001276760.2:c.728G>T
NM_001276761.2:c.728G>T
NM_000546.6:c.845G>T
NM_001126112.3:c.845G>T
NM_001126113.3:c.845G>T
NM_001126114.3:c.845G>T
NM_001126115.2:c.449G>T
NM_001126116.2:c.449G>T
NM_001126117.2:c.449G>T
NM_001126118.2:c.728G>T
NM_001276695.3:c.728G>T
NM_001276696.3:c.728G>T
NM_001276697.3:c.368G>T
NM_001276698.3:c.368G>T
NM_001276699.3:c.368G>T
NM_001276760.3:c.728G>T
NM_001276761.3:c.728G>T
NC_000017.11:g.7673775C>A
CM000679.2:g.7673775C>A
NC_000017.10:g.7577093C>A
CM000679.1:g.7577093C>A
NC_000017.9:g.7517818C>A
NG_017013.2:g.18776G>T
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Uncertain Significance

Met criteria codes 4
PM1 PP3_Moderate BS3 PM2_Supporting
Not Met criteria codes 13
BA1 PS2 PS4 PS3 PS1 PP1 PM6 PM5 BS2 BS4 BS1 BP2 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is absent from the gnomAD non-cancer v2.1.1 dataset (PM2_supporting). Transactivation assays show retained function according to Kato, et al (PMID: 12826609) and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (PMID: 30224644) (BS3). Additionally, this variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_moderate). Codon 282 is considered a hotspot (PM1) per the revised TP53 classification rules (PMID: 33300245). In summary, TP53 c.845G>T; p.Arg282Leu meets criteria to be classified as uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_supporting; PP3_moderate; PM1; BS3.
Met criteria codes
PM1
Codon 282 is considered a hotspot. Cancer hotspots website describes 1 somatic occurrence of R282L (does not reach threshold of 10, as set by the ClinGen TP53 group)
PP3_Moderate
Align-GVGD class = C65 + BayesDel = 0.360452
BS3
Kato (functional), no LOF by Kotler (-1.758), Giacomelli (notDNE_notLOF)
PM2_Supporting
Not found in gnomAD dataset v2.1.1
Not Met criteria codes
BA1
Not found in gnomAD dataset v2.1.1
PS2
No data available
PS4
None
PS3
Kato (functional), no LOF by Kotler (-1.758), Giacomelli (notDNE_notLOF)
PS1
There is no previously established pathogenic variant p.R282L with a different nucleotide change. varSEAK predicts no splicing effect (Class 1)
PP1
No data available
PM6
No data available
PM5
Code was not scored since codon 282 is a hotspot (met PM1)
BS2
None
BS4
Lab C = pt with H2 neg breast dx 30s, mom NEGATIVE breast dx 50s
BS1
Not found in gnomAD dataset v2.1.1
BP2
No data available
BP4
Align-GVGD class = C65 + BayesDel = 0.360452
Curation History
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