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.641A>G (p.His214Arg)

CA16040595

376615 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b36419d2-274a-4464-b4c9-c0ff2471c0d9

HGVS expressions

NM_000546.5:c.641A>G

NM_000546.5(TP53):c.641A>G (p.His214Arg)

NC_000017.11:g.7674890T>C

CM000679.2:g.7674890T>C

NC_000017.10:g.7578208T>C

CM000679.1:g.7578208T>C

NC_000017.9:g.7518933T>C

NG_017013.2:g.17661A>G

ENST00000269305.9:c.641A>G

ENST00000269305.8:c.641A>G

ENST00000359597.8:n.641A>G

ENST00000413465.6:n.641A>G

ENST00000420246.6:c.641A>G

ENST00000445888.6:c.641A>G

ENST00000455263.6:c.641A>G

ENST00000504290.5:c.245A>G

ENST00000504937.5:c.245A>G

ENST00000505014.5:n.897A>G

ENST00000509690.5:c.245A>G

ENST00000510385.5:c.245A>G

ENST00000514944.5:c.362A>G

ENST00000574684.1:n.67+163A>G

ENST00000610292.4:c.524A>G

ENST00000610538.4:c.524A>G

ENST00000610623.4:c.164A>G

ENST00000615910.4:n.608A>G

ENST00000617185.4:c.641A>G

ENST00000618944.4:c.164A>G

ENST00000619186.4:c.164A>G

ENST00000619485.4:c.524A>G

ENST00000620739.4:c.524A>G

ENST00000622645.4:c.524A>G

ENST00000635293.1:c.524A>G

NM_001126112.2:c.641A>G

NM_001126113.2:c.641A>G

NM_001126114.2:c.641A>G

NM_001126115.1:c.245A>G

NM_001126116.1:c.245A>G

NM_001126117.1:c.245A>G

NM_001126118.1:c.524A>G

NM_001276695.1:c.524A>G

NM_001276696.1:c.524A>G

NM_001276697.1:c.164A>G

NM_001276698.1:c.164A>G

NM_001276699.1:c.164A>G

NM_001276760.1:c.524A>G

NM_001276761.1:c.524A>G

NM_001276695.2:c.524A>G

NM_001276696.2:c.524A>G

NM_001276697.2:c.164A>G

NM_001276698.2:c.164A>G

NM_001276699.2:c.164A>G

NM_001276760.2:c.524A>G

NM_001276761.2:c.524A>G

NM_000546.6:c.641A>G

NM_001126112.3:c.641A>G

NM_001126113.3:c.641A>G

NM_001126114.3:c.641A>G

NM_001126115.2:c.245A>G

NM_001126116.2:c.245A>G

NM_001126117.2:c.245A>G

NM_001126118.2:c.524A>G

NM_001276695.3:c.524A>G

NM_001276696.3:c.524A>G

NM_001276697.3:c.164A>G

NM_001276698.3:c.164A>G

NM_001276699.3:c.164A>G

NM_001276760.3:c.524A>G

NM_001276761.3:c.524A>G

NM_000546.6(TP53):c.641A>G (p.His214Arg)

Likely Pathogenic

PM2_Supporting PS3 PM1 PS4_Supporting

BS3 BP4 PP3

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 absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). 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, this variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 20522432, ClinVar SCV000581129.3). In summary, TP53 c.641A>G; p.His214Arg 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, PS3, PM1, PS4_Supporting.

PM2_Supporting

absent in population databases

PS3

Non-functional allele according to T-A assays in IARC; one study also shows loss of growth suppression in colony formation assays

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

Study shows loss of growth suppression in colony formation assays PubMed:11920959

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

PM1

35 somatic variants reported in cancerhotspots.org

PS4_Supporting

1 proband from literature meeting Chompret = 0.5 pt; 1 proband from EP member meeting Chompret (ClinVar SCV000581129.3) = 0.5 pt; total 1 pts

1 proband meeting Chompret PubMed:20522432

BS3

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

BP4

BayesDel and AGVGD are not concordant

PP3

BayesDel and AGVGD are not concordant

Approved on: 2022-06-27

Published on: 2022-06-27

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