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.993+1delG

CA645369685

428898 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a608c703-2232-4c79-86dd-00844776434d

HGVS expressions

NM_000546.5:c.993+1delG

NM_000546.5(TP53):c.993+1delG

NC_000017.11:g.7673535del

CM000679.2:g.7673535del

NC_000017.10:g.7576853del

CM000679.1:g.7576853del

NC_000017.9:g.7517578del

NG_017013.2:g.19017del

NM_000546.5:c.993+1del

NM_001126112.2:c.993+1del

NM_001126113.2:c.993+1del

NM_001126114.2:c.993+1del

NM_001126115.1:c.597+1del

NM_001126116.1:c.597+1del

NM_001126117.1:c.597+1del

NM_001126118.1:c.876+1del

NM_001276695.1:c.876+1del

NM_001276696.1:c.876+1del

NM_001276697.1:c.516+1del

NM_001276698.1:c.516+1del

NM_001276699.1:c.516+1del

NM_001276760.1:c.876+1del

NM_001276761.1:c.876+1del

ENST00000269305.8:c.993+1del

ENST00000359597.8:n.993+1del

ENST00000413465.6:n.782+647del

ENST00000420246.6:c.993+1del

ENST00000445888.6:c.993+1del

ENST00000455263.6:c.993+1del

ENST00000504290.5:c.597+1del

ENST00000504937.5:c.597+1del

ENST00000510385.5:c.597+1del

ENST00000576024.1:n.53+1del

ENST00000610292.4:c.876+1del

ENST00000610538.4:c.876+1del

ENST00000610623.4:c.516+1del

ENST00000615910.4:n.960+1del

ENST00000617185.4:c.993+1del

ENST00000618944.4:c.516+1del

ENST00000619186.4:c.516+1del

ENST00000619485.4:c.876+1del

ENST00000620739.4:c.876+1del

ENST00000622645.4:c.876+1del

ENST00000635293.1:c.876+1del

Pathogenic

PS4_Supporting PM2_Supporting PVS1 PP1_Moderate

PM6

Evidence Links 1

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

The c.993+1delG variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in a proband meeting Classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 10980596). This variant was found to co-segregation with disease in multiple affected family members, with 5 meioses observed (PP1_Moderate; PMID: 10980596). In summary, TP53 c.993+1delG meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1, PM2_Supporting, PS4_Supporting, PP1_Moderate.

PS4_Supporting

One Classic LFS family reported.

Proband with brain tumor at age 10. Father brain tumor at age 32. Paternal aunt with brain tumor at age 33. Paternal uncle with soft tissue sarcoma tumor at age 2. Paternal grandmother with breast cancer at age 28. Other LFS cancers in family. Proband = 1 point PubMed:10980596

PM2_Supporting

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

PVS1

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

PP1_Moderate

1 Classic LFS family with 5 meioses

Classic LFS family with 5 meioses PubMed:10980596

PM6

Clinical case submitted from EP member: proband w/breast cancer at age 22. Criteria met but not used since data was unpublished and variant already meets pathogenic.

Approved on: 2019-08-28

Published on: 2020-01-24

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