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

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
BS3
Kato (functional), no LOF by Kotler (-1.758), Giacomelli (notDNE_notLOF)
PP3_Moderate
Align-GVGD class = C65 + BayesDel = 0.360452
PM2_Supporting
Not found in gnomAD dataset v2.1.1
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)
Not Met criteria codes
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)
PP1
No data available
PM5
Code was not scored since codon 282 is a hotspot (met PM1)
PM6
No data available
BA1
Not found in gnomAD dataset v2.1.1
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.