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>A (p.Arg248Gln)

CA000387

12356 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: cf887752-8539-4177-a74d-dc5c8f8a36ed
Approved on: 2019-08-28
Published on: 2020-01-24

HGVS expressions

NM_000546.5:c.743G>A
NM_000546.5(TP53):c.743G>A (p.Arg248Gln)
NC_000017.11:g.7674220C>T
CM000679.2:g.7674220C>T
NC_000017.10:g.7577538C>T
CM000679.1:g.7577538C>T
NC_000017.9:g.7518263C>T
NG_017013.2:g.18331G>A
ENST00000503591.2:c.743G>A
ENST00000508793.6:c.743G>A
ENST00000509690.6:c.347G>A
ENST00000514944.6:c.464G>A
ENST00000604348.6:c.722G>A
ENST00000269305.9:c.743G>A
ENST00000269305.8:c.743G>A
ENST00000359597.8:c.743G>A
ENST00000413465.6:c.743G>A
ENST00000420246.6:c.743G>A
ENST00000445888.6:c.743G>A
ENST00000455263.6:c.743G>A
ENST00000504290.5:c.347G>A
ENST00000504937.5:c.347G>A
ENST00000509690.5:c.347G>A
ENST00000510385.5:c.347G>A
ENST00000514944.5:c.464G>A
ENST00000610292.4:c.626G>A
ENST00000610538.4:c.626G>A
ENST00000610623.4:c.266G>A
ENST00000615910.4:c.710G>A
ENST00000617185.4:c.743G>A
ENST00000618944.4:c.266G>A
ENST00000619186.4:c.266G>A
ENST00000619485.4:c.626G>A
ENST00000620739.4:c.626G>A
ENST00000622645.4:c.626G>A
ENST00000635293.1:c.626G>A
NM_001126112.2:c.743G>A
NM_001126113.2:c.743G>A
NM_001126114.2:c.743G>A
NM_001126115.1:c.347G>A
NM_001126116.1:c.347G>A
NM_001126117.1:c.347G>A
NM_001126118.1:c.626G>A
NM_001276695.1:c.626G>A
NM_001276696.1:c.626G>A
NM_001276697.1:c.266G>A
NM_001276698.1:c.266G>A
NM_001276699.1:c.266G>A
NM_001276760.1:c.626G>A
NM_001276761.1:c.626G>A
NM_001276695.2:c.626G>A
NM_001276696.2:c.626G>A
NM_001276697.2:c.266G>A
NM_001276698.2:c.266G>A
NM_001276699.2:c.266G>A
NM_001276760.2:c.626G>A
NM_001276761.2:c.626G>A
NM_000546.6:c.743G>A
NM_001126112.3:c.743G>A
NM_001126113.3:c.743G>A
NM_001126114.3:c.743G>A
NM_001126115.2:c.347G>A
NM_001126116.2:c.347G>A
NM_001126117.2:c.347G>A
NM_001126118.2:c.626G>A
NM_001276695.3:c.626G>A
NM_001276696.3:c.626G>A
NM_001276697.3:c.266G>A
NM_001276698.3:c.266G>A
NM_001276699.3:c.266G>A
NM_001276760.3:c.626G>A
NM_001276761.3:c.626G>A
More

Pathogenic

Met criteria codes 5
PS2 PS3 PS4 PP3 PM1
Not Met criteria codes 5
BA1 PP1 PM2 BS1 BP4

Evidence Links 5

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). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). 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 at least 3 probands meeting Classic Li-Fraumeni syndrome and 2 probands meeting Chompret criteria (PS4; PMID: 1565143, 9242456, 15381368, 7887414). There is a de novo observation of a proband with adrenocortical carcinoma with parental confirmation (PS2; PMID: 15381368). In summary, TP53 c.743G>A; p.Arg248Gln 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, PP3, PS3, PS4, PS2.
Met criteria codes
PS2
2 pts assigned for Bendig, et al 2004 case
Proband with ACC at age 7yr. Parents were negative for variant and other markers were assessed in both parents to confirm paternity but maternity was also confirmed in the process. 2 points assigned. PubMed:15381368
PS3
Low function on T-A assay and p53 mouse models displaying gain of function in tumorigenesis.
Two hot spot mutation p53 mouse models display differential gain of function in tumorigenesis. They made both a heterozygous R248Q/null mouse and a homozygous Q/Q mouse. Both had similar rapid tumor development, even when compared to -/- mice. PubMed:23538418
PS4
3 probands meeting Classic criteria and 2 probands meeting Chrompret criteria. 4 total points.
Proband with choroid plexus tumor at age 1 year. Mother with bilateral breast cancer at age 26 and 38, lymphoma at age 32 and lung cancer at age 38. Both were sequenced and found to harbor variant. Meets Chrompret criteria. PubMed:7887414
Classic LFS family (1): Proband with osteosarcoma at age 17 and breast cancer at 28. Her daughter has rhabdomyosarcoma at age 5 yr. PubMed:1565143
Classic LFS family (222): Proband with rhabdomyosarcoma at age 3 yrs, mother with breast cancer at age 33, brother with sarcoma at age 14. PubMed:9242456
Proband with ACC at age 7yr. Parents were negative for variant and other markers were assessed in both parents to confirm paternity but maternity was also confirmed in the process. Meets Chrompret criteria PubMed:15381368
PP3
BayesDel & AGVGD concordant
PM1
Codon 248 is a hotspot
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
Only 6 meiosis among several families at this point.
1 segregation: Proband with choroid plexus tumor at age 1 year. Mother with bilateral breast cancer at age 26 and 38, lymphoma at age 32 and lung cancer at age 38. Both were sequenced and found to harbor variant. PubMed:7887414
Family 222 - 2 segregations: Proband with rhabdomyosarcoma at age 3 yrs, mother with breast cancer at age 33, brother with sarcoma at age 14. Each genotyped. PubMed:9242456
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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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