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.537T>A (p.His179Gln)

CA16615708

406578 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2f0057b7-4b8d-4b05-98bd-c7760ee4259c

HGVS expressions

NM_000546.5:c.537T>A

NM_000546.5(TP53):c.537T>A (p.His179Gln)

NC_000017.11:g.7675075A>T

CM000679.2:g.7675075A>T

NC_000017.10:g.7578393A>T

CM000679.1:g.7578393A>T

NC_000017.9:g.7519118A>T

NG_017013.2:g.17476T>A

NM_001126112.2:c.537T>A

NM_001126113.2:c.537T>A

NM_001126114.2:c.537T>A

NM_001126115.1:c.141T>A

NM_001126116.1:c.141T>A

NM_001126117.1:c.141T>A

NM_001126118.1:c.420T>A

NM_001276695.1:c.420T>A

NM_001276696.1:c.420T>A

NM_001276697.1:c.60T>A

NM_001276698.1:c.60T>A

NM_001276699.1:c.60T>A

NM_001276760.1:c.420T>A

NM_001276761.1:c.420T>A

ENST00000269305.8:c.537T>A

ENST00000359597.8:n.537T>A

ENST00000413465.6:n.537T>A

ENST00000420246.6:c.537T>A

ENST00000445888.6:c.537T>A

ENST00000455263.6:c.537T>A

ENST00000504290.5:c.141T>A

ENST00000504937.5:c.141T>A

ENST00000505014.5:n.793T>A

ENST00000509690.5:c.141T>A

ENST00000510385.5:c.141T>A

ENST00000514944.5:c.258T>A

ENST00000574684.1:n.45T>A

ENST00000610292.4:c.420T>A

ENST00000610538.4:c.420T>A

ENST00000610623.4:c.60T>A

ENST00000615910.4:n.504T>A

ENST00000617185.4:c.537T>A

ENST00000618944.4:c.60T>A

ENST00000619186.4:c.60T>A

ENST00000619485.4:c.420T>A

ENST00000620739.4:c.420T>A

ENST00000622645.4:c.420T>A

ENST00000635293.1:c.420T>A

Pathogenic

PM2_Supporting PS3 PP3 PM6 PM1

PS4 BA1 BS1 BP4

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 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 >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Additionally, there was a de novo observation in an individual with two Li-Fraumeni syndrome spectrum tumors under the age of 5 years without mention of maternal confirmation (PM6; PMID: 19556618). In summary, TP53 c.537T>A; p.His179Gln meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PS3, PM1, PM6.

PM2_Supporting

Absent in population databases

PS3

Non-functional allele according to T-A assays in IARC and evidence of DNE & LOF in Giacomelli, et al data

Evidence of DNE or LOF in Giacomelli, et al data PubMed:30224644

Non-functional variant on T-A assays according to Kato, et al PubMed:12826609

PP3

BayesDel & AGVGD are concordant

PM6

Proband with H179Q and 2 LFS-spectrum cancers under age 5, mutation de novo, paternity (but not maternity) confirmed.

PM1

Variant observed 12 times in cancerhotspots.org

PS4

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

BA1

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

Approved on: 2019-08-28

Published on: 2020-01-24

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