Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

Variant: NM_000546.5(TP53):c.742C>T (p.Arg248Trp)

CA000382

12347 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 55c3283e-f0f6-4e18-b837-99a275ea7d90

HGVS expressions

NM_000546.5:c.742C>T

NM_000546.5(TP53):c.742C>T (p.Arg248Trp)

NC_000017.11:g.7674221G>A

CM000679.2:g.7674221G>A

NC_000017.10:g.7577539G>A

CM000679.1:g.7577539G>A

NC_000017.9:g.7518264G>A

NG_017013.2:g.18330C>T

NM_001126112.2:c.742C>T

NM_001126113.2:c.742C>T

NM_001126114.2:c.742C>T

NM_001126115.1:c.346C>T

NM_001126116.1:c.346C>T

NM_001126117.1:c.346C>T

NM_001126118.1:c.625C>T

NM_001276695.1:c.625C>T

NM_001276696.1:c.625C>T

NM_001276697.1:c.265C>T

NM_001276698.1:c.265C>T

NM_001276699.1:c.265C>T

NM_001276760.1:c.625C>T

NM_001276761.1:c.625C>T

ENST00000269305.8:c.742C>T

ENST00000359597.8:n.742C>T

ENST00000413465.6:n.742C>T

ENST00000420246.6:c.742C>T

ENST00000445888.6:c.742C>T

ENST00000455263.6:c.742C>T

ENST00000504290.5:c.346C>T

ENST00000504937.5:c.346C>T

ENST00000509690.5:c.346C>T

ENST00000510385.5:c.346C>T

ENST00000514944.5:c.463C>T

ENST00000610292.4:c.625C>T

ENST00000610538.4:c.625C>T

ENST00000610623.4:c.265C>T

ENST00000615910.4:n.709C>T

ENST00000617185.4:c.742C>T

ENST00000618944.4:c.265C>T

ENST00000619186.4:c.265C>T

ENST00000619485.4:c.625C>T

ENST00000620739.4:c.625C>T

ENST00000622645.4:c.625C>T

ENST00000635293.1:c.625C>T

Pathogenic

PP1_Strong PP3_Moderate PS3 PS2 PS4 PM1

Evidence Links 4

Expert Panel

TP53 VCEP

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: 20182602). 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 at least 3 probands with Classic Li-Fraumeni syndrome criteria and 2 probands meeting Chrompret criteria (PS4; PMID: 8425176, 20522432, 23667202, 9242456). This variant was found to co-segregate with disease in multiple affected family members, with >7 meioses observed across at least two families (PP1_Strong; PMID: 1978757, 9825943). There is a de novo observation of a proband with a rhabdomyosarcoma with parental confirmation (PS2; PMID: 10089074). In summary, TP53 c.742C>T; p.Arg248Trp 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_Moderate, PS3, PS4, PP1_Strong, PS2.

PP1_Strong

Total of 7 meioses b/w 2 families

PP3_Moderate

AGVGD score of C65 and BayesDel score is >0.16

PS3

T-A assays show non-functional allele; colon formation assay and mouse model suggest pathogenicity

PS2

2yo w/rhabdo with parental confirmation

PS4

3 proband w/LFS = 3 pts; 2 probands w/Chompret = 1 pts; total 4 pts

1 proband meeting Chompret. Proband = 0.5 point PubMed:23667202

Proband with rhabdomyosarcoma at age 2 and osteosarcoma at age 20. Mother had breast cancer at age 31. Proband = 1 point PubMed:8425176

1 proband meeting LFS classic and 1 proband meeting Chompret. Proband = 1.5 pts PubMed:20522432

Proband with rhabdomyosarcoma at age 3, chondrosarcoma at age 14 and melanoma at age 15. Mother with breast cancer at age 33 and sister with adrenocortical carcinoma at age 1 and breast cancer at age 29. Proband = 1 point PubMed:9242456

PM1

Codon 248 is a hotspot

Approved on: 2019-08-28

Published on: 2020-01-24

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