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_000546.5(TP53):c.743G>T (p.Arg248Leu)

CA10580924

230253 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 291eceb4-ecb0-489a-b637-b9ff4f5f34d5
Approved on: 2019-08-28
Published on: 2020-01-24

HGVS expressions

NM_000546.5:c.743G>T
NM_000546.5(TP53):c.743G>T (p.Arg248Leu)
NC_000017.11:g.7674220C>A
CM000679.2:g.7674220C>A
NC_000017.10:g.7577538C>A
CM000679.1:g.7577538C>A
NC_000017.9:g.7518263C>A
NG_017013.2:g.18331G>T
ENST00000503591.2:c.743G>T
ENST00000508793.6:c.743G>T
ENST00000509690.6:c.347G>T
ENST00000514944.6:c.464G>T
ENST00000604348.6:c.722G>T
ENST00000269305.9:c.743G>T
ENST00000269305.8:c.743G>T
ENST00000359597.8:c.743G>T
ENST00000413465.6:c.743G>T
ENST00000420246.6:c.743G>T
ENST00000445888.6:c.743G>T
ENST00000455263.6:c.743G>T
ENST00000504290.5:c.347G>T
ENST00000504937.5:c.347G>T
ENST00000509690.5:c.347G>T
ENST00000510385.5:c.347G>T
ENST00000514944.5:c.464G>T
ENST00000610292.4:c.626G>T
ENST00000610538.4:c.626G>T
ENST00000610623.4:c.266G>T
ENST00000615910.4:c.710G>T
ENST00000617185.4:c.743G>T
ENST00000618944.4:c.266G>T
ENST00000619186.4:c.266G>T
ENST00000619485.4:c.626G>T
ENST00000620739.4:c.626G>T
ENST00000622645.4:c.626G>T
ENST00000635293.1:c.626G>T
NM_001126112.2:c.743G>T
NM_001126113.2:c.743G>T
NM_001126114.2:c.743G>T
NM_001126115.1:c.347G>T
NM_001126116.1:c.347G>T
NM_001126117.1:c.347G>T
NM_001126118.1:c.626G>T
NM_001276695.1:c.626G>T
NM_001276696.1:c.626G>T
NM_001276697.1:c.266G>T
NM_001276698.1:c.266G>T
NM_001276699.1:c.266G>T
NM_001276760.1:c.626G>T
NM_001276761.1:c.626G>T
NM_001276695.2:c.626G>T
NM_001276696.2:c.626G>T
NM_001276697.2:c.266G>T
NM_001276698.2:c.266G>T
NM_001276699.2:c.266G>T
NM_001276760.2:c.626G>T
NM_001276761.2:c.626G>T
NM_000546.6:c.743G>T
NM_001126112.3:c.743G>T
NM_001126113.3:c.743G>T
NM_001126114.3:c.743G>T
NM_001126115.2:c.347G>T
NM_001126116.2:c.347G>T
NM_001126117.2:c.347G>T
NM_001126118.2:c.626G>T
NM_001276695.3:c.626G>T
NM_001276696.3:c.626G>T
NM_001276697.3:c.266G>T
NM_001276698.3:c.266G>T
NM_001276699.3:c.266G>T
NM_001276760.3:c.626G>T
NM_001276761.3:c.626G>T
More

Pathogenic

Met criteria codes 5
PS3 PS4_Supporting PM1 PP3_Moderate PM2_Supporting
Not Met criteria codes 1
BP4

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). It 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). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in 1 family meeting Classic Li-Fraumeni syndrome and 1 proband meeting Chompret criteria (PS4_Supporting; PMID: 1359493, 25584008). In summary, TP53 c.743G>T; p.Arg248Leu meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting.
Met criteria codes
PS3
Non-functional allele according to T-A assays in IARC; colony formation assay showed no growth suppression.
PS4_Supporting
1 LFS family and 1 Chompret family = 1.5 points
Proband with ACC at 6 months of age. No mention of family history, but meets at least Chompret criteria. Proband = 0.5 point PubMed:25584008
Variant was identified in two full siblings with a brain tumor and rhabdomyosarcoma and a maternal half sister with a tumor of unknown origin. Their mother was found to be mosaic for the variant. Proband =1 point PubMed:1359493
PM1
Codon 248 is a hotspot
Codon 248 is a hotspot PubMed:2046748
PP3_Moderate
AGVGD score is C65 and BayesDel score is >0.16
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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