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.488A>G (p.Tyr163Cys)

CA000240

127814 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8a807387-daa0-4fb9-86e1-7e5ad3d1217f

HGVS expressions

NM_000546.5:c.488A>G

NM_000546.5(TP53):c.488A>G (p.Tyr163Cys)

NC_000017.11:g.7675124T>C

CM000679.2:g.7675124T>C

NC_000017.10:g.7578442T>C

CM000679.1:g.7578442T>C

NC_000017.9:g.7519167T>C

NG_017013.2:g.17427A>G

NM_001126112.2:c.488A>G

NM_001126113.2:c.488A>G

NM_001126114.2:c.488A>G

NM_001126115.1:c.92A>G

NM_001126116.1:c.92A>G

NM_001126117.1:c.92A>G

NM_001126118.1:c.371A>G

NM_001276695.1:c.371A>G

NM_001276696.1:c.371A>G

NM_001276697.1:c.11A>G

NM_001276698.1:c.11A>G

NM_001276699.1:c.11A>G

NM_001276760.1:c.371A>G

NM_001276761.1:c.371A>G

ENST00000269305.8:c.488A>G

ENST00000359597.8:n.488A>G

ENST00000413465.6:n.488A>G

ENST00000420246.6:c.488A>G

ENST00000445888.6:c.488A>G

ENST00000455263.6:c.488A>G

ENST00000504290.5:c.92A>G

ENST00000504937.5:c.92A>G

ENST00000505014.5:n.744A>G

ENST00000508793.5:c.488A>G

ENST00000509690.5:c.92A>G

ENST00000510385.5:c.92A>G

ENST00000514944.5:c.209A>G

ENST00000610292.4:c.371A>G

ENST00000610538.4:c.371A>G

ENST00000610623.4:c.11A>G

ENST00000615910.4:n.455A>G

ENST00000617185.4:c.488A>G

ENST00000618944.4:c.11A>G

ENST00000619186.4:c.11A>G

ENST00000619485.4:c.371A>G

ENST00000620739.4:c.371A>G

ENST00000622645.4:c.371A>G

ENST00000635293.1:c.371A>G

Pathogenic

PM1 PP3_Moderate PS4_Supporting PM2_Supporting PS2_Moderate PS3

Evidence Links 2

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

This variant 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). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). 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 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 21601526, 8164043). Additionally, there is one proband with a de novo observation of a Li-Fraumeni syndrome core cancer under the age of 5 years with parental confirmation (PS2_Moderate; PMID: 19556618). In summary, the clinical significance of TP53 c.488A>G; p.Tyr163Cys is pathogenic for Li-Fraumeni syndrome: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PS2_Moderate.

PM1

Observed 54 times in cancerhotspots.org

PP3_Moderate

AGVGD score is C65 and BayesDel score is >0.16

PS4_Supporting

2 probands meeting Chompret criteria = 1 point

Proband with ACC at 2 and brain tumor T 5 yr PubMed:21601526

Proband w/osteosarcoma whose mother was diagnosed with brain tumor <45 yrs of age. PubMed:8164043

PM2_Supporting

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS2_Moderate

Variant found in child with 1 LFS cancer under the age of 5yrs. Parents wt with paternal confirmation.

PS3

Functional allele according to T-A assays in IARC; colony formation assay showed decreased growth suppression.

Approved on: 2019-08-28

Published on: 2020-01-24

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