Evidence Repository
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
Link to MONDO
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
More

Uncertain Significance

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

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)
BS3
Kato (functional), no LOF by Kotler (-1.758), Giacomelli (notDNE_notLOF)
PM2_Supporting
Not found in gnomAD dataset v2.1.1
PP3_Moderate
Align-GVGD class = C65 + BayesDel = 0.360452
Not Met criteria codes
PP1
No data available
PM6
No data available
PM5
Code was not scored since codon 282 is a hotspot (met PM1)
BA1
Not found in gnomAD dataset v2.1.1
BS4
Lab C = pt with H2 neg breast dx 30s, mom NEGATIVE breast dx 50s
BS1
Not found in gnomAD dataset v2.1.1
BS2
None
BP2
No data available
BP4
Align-GVGD class = C65 + BayesDel = 0.360452
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)
Curation History
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