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.659A>G (p.Tyr220Cys)

CA000315

127819 (ClinVar)

Gene: TP53

Condition: Li-Fraumeni syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4795612b-c5d2-4229-a5ec-172fedfbcf55

HGVS expressions

NM_000546.5:c.659A>G

NM_000546.5(TP53):c.659A>G (p.Tyr220Cys)

NC_000017.11:g.7674872T>C

CM000679.2:g.7674872T>C

NC_000017.10:g.7578190T>C

CM000679.1:g.7578190T>C

NC_000017.9:g.7518915T>C

NG_017013.2:g.17679A>G

NM_001126112.2:c.659A>G

NM_001126113.2:c.659A>G

NM_001126114.2:c.659A>G

NM_001126115.1:c.263A>G

NM_001126116.1:c.263A>G

NM_001126117.1:c.263A>G

NM_001126118.1:c.542A>G

NM_001276695.1:c.542A>G

NM_001276696.1:c.542A>G

NM_001276697.1:c.182A>G

NM_001276698.1:c.182A>G

NM_001276699.1:c.182A>G

NM_001276760.1:c.542A>G

NM_001276761.1:c.542A>G

ENST00000269305.8:c.659A>G

ENST00000359597.8:n.659A>G

ENST00000413465.6:n.659A>G

ENST00000420246.6:c.659A>G

ENST00000445888.6:c.659A>G

ENST00000455263.6:c.659A>G

ENST00000504290.5:c.263A>G

ENST00000504937.5:c.263A>G

ENST00000505014.5:n.915A>G

ENST00000509690.5:c.263A>G

ENST00000510385.5:c.263A>G

ENST00000514944.5:c.380A>G

ENST00000574684.1:n.67+181A>G

ENST00000610292.4:c.542A>G

ENST00000610538.4:c.542A>G

ENST00000610623.4:c.182A>G

ENST00000615910.4:n.626A>G

ENST00000617185.4:c.659A>G

ENST00000618944.4:c.182A>G

ENST00000619186.4:c.182A>G

ENST00000619485.4:c.542A>G

ENST00000620739.4:c.542A>G

ENST00000622645.4:c.542A>G

ENST00000635293.1:c.542A>G

Pathogenic

PM6 PM1 PP3_Moderate PP1_Strong PS3 PS4

Evidence Links 7

Expert Panel

TP53 VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

TP53 VCEP

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 are two assays demonstrating loss of function. One study demonstrates a structural defect that destabilizes the protein and another study showed essentially no apoptosis activity in mutant cells (PS3; PMID: 12826609, 20516128, 15037740). This variant has been reported in at least 4 probands meeting Classic Li-Fraumeni syndrome criteria (PS4; PMID: 8118819, 10432928, 10589545, 15977174). 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: 15977174, 9242456, 19101993, 10432928). Additionally, there was a de novo observation in an individual with 10 Classic Li-Fraumeni syndrome spectrum tumors without mention of parental confirmation (PM6; PMID: 18307025). In summary, TP53 c.659A>G; p.Tyr220Cys meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3_Moderate, PM1, PS3, PS4, PP1_Strong, PM6.

PM6

Variant identified in proband with 10 LFS cancers, including osteosarcoma at age 15. Variant not found in parents but parental testing not mentioned.

PM1

127 observations in cancerhotspots.org

PP3_Moderate

BayesDel score >0.16 & AGVGD = Class C65

PP1_Strong

>7 segregations between PMID: 15977174, 9242456, 19101993, 10432928

PS3

T-A assays suggest non-functional allele; mutant allele shows no apoptosis activity; there is evidence of DNE & LOF in Giacomelli, et al data

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

mutant allele shows essentially no apoptosis activity PubMed:15037740

There is evidence of DNE & LOF in Giacomelli, et al data PubMed:30224644

PS4

4 LFS families (PMID: 8118819, 10432928, 10589545, 15977174) = 4 pts

1 Classic family: proband with anaplastic astrocytoma, brother with sarcoma at 28 yr, sister with breast at 22 yr and colon at 26 yr and father with mediastinal cancer at 40 yr and esophageal at 70 yr. PubMed:10589545

1 Classic family: This variant was identified in 1 individual with a choroid plexus papilloma at age 4. He inherited the variant from his mother who had an osteosarcoma at age 13 and bilateral breast cancer at age 36. PubMed:10432928

1 Classic family: Mother with breast cancer at age 27. One with adrenocortical carcinoma at age 1, and another child had a rhabdomyosarcoma at age 1. PubMed:8118819

1 Classic family: Mother with adenocarcinoma at 34, son with rhabdomyosarcoma at age 2, daughter with 3 osteosarcomas by age 9 and another daughter with osteosarcoma at age 14. PubMed:15977174

Approved on: 2019-08-28

Published on: 2020-01-24

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