Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.517G>A (p.Val173Met)

CA10577579

233951 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 29aaaea7-f2a2-441a-911c-111485dd6b50
Approved on: 2019-08-28
Published on: 2020-01-24

HGVS expressions

NM_000546.5:c.517G>A
NM_000546.5(TP53):c.517G>A (p.Val173Met)
NC_000017.11:g.7675095C>T
CM000679.2:g.7675095C>T
NC_000017.10:g.7578413C>T
CM000679.1:g.7578413C>T
NC_000017.9:g.7519138C>T
NG_017013.2:g.17456G>A
ENST00000503591.2:c.517G>A
ENST00000508793.6:c.517G>A
ENST00000509690.6:c.121G>A
ENST00000514944.6:c.238G>A
ENST00000604348.6:c.496G>A
ENST00000269305.9:c.517G>A
ENST00000269305.8:c.517G>A
ENST00000359597.8:c.517G>A
ENST00000413465.6:c.517G>A
ENST00000420246.6:c.517G>A
ENST00000445888.6:c.517G>A
ENST00000455263.6:c.517G>A
ENST00000504290.5:c.121G>A
ENST00000504937.5:c.121G>A
ENST00000505014.5:n.773G>A
ENST00000509690.5:c.121G>A
ENST00000510385.5:c.121G>A
ENST00000514944.5:c.238G>A
ENST00000574684.1:n.25G>A
ENST00000610292.4:c.400G>A
ENST00000610538.4:c.400G>A
ENST00000610623.4:c.40G>A
ENST00000615910.4:c.484G>A
ENST00000617185.4:c.517G>A
ENST00000618944.4:c.40G>A
ENST00000619186.4:c.40G>A
ENST00000619485.4:c.400G>A
ENST00000620739.4:c.400G>A
ENST00000622645.4:c.400G>A
ENST00000635293.1:c.400G>A
NM_001126112.2:c.517G>A
NM_001126113.2:c.517G>A
NM_001126114.2:c.517G>A
NM_001126115.1:c.121G>A
NM_001126116.1:c.121G>A
NM_001126117.1:c.121G>A
NM_001126118.1:c.400G>A
NM_001276695.1:c.400G>A
NM_001276696.1:c.400G>A
NM_001276697.1:c.40G>A
NM_001276698.1:c.40G>A
NM_001276699.1:c.40G>A
NM_001276760.1:c.400G>A
NM_001276761.1:c.400G>A
NM_001276695.2:c.400G>A
NM_001276696.2:c.400G>A
NM_001276697.2:c.40G>A
NM_001276698.2:c.40G>A
NM_001276699.2:c.40G>A
NM_001276760.2:c.400G>A
NM_001276761.2:c.400G>A
NM_000546.6:c.517G>A
NM_001126112.3:c.517G>A
NM_001126113.3:c.517G>A
NM_001126114.3:c.517G>A
NM_001126115.2:c.121G>A
NM_001126116.2:c.121G>A
NM_001126117.2:c.121G>A
NM_001126118.2:c.400G>A
NM_001276695.3:c.400G>A
NM_001276696.3:c.400G>A
NM_001276697.3:c.40G>A
NM_001276698.3:c.40G>A
NM_001276699.3:c.40G>A
NM_001276760.3:c.400G>A
NM_001276761.3:c.400G>A
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Pathogenic

Met criteria codes 6
PS2 PS3 PP3 PM1 PS4_Supporting PM2_Supporting

Evidence Links 4

Expert Panel

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). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). 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 a proband meeting Classic Li-Fraumeni syndrome criteria (PS4_Supporting; PMID: 16494995). There is a de novo observation of a proband with a diagnosis of a sarcoma, breast cancer and thyroid cancers under the age of 26 years with parental confirmation (PS2; ClinVar SCV000545293.4). In summary, TP53 p.Val173Met meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PM1, PS3, PS4_Supporting, PS2.
Met criteria codes
PS2
Clinical case from EP member w/sarcoma @ 12, breast @ 23 and thyroid @ 26
PS3
Non-functional allele according to T-A assays in IARC; essentially no apoptosis activity in mutant cells; evidence of DNE & LOF in Giacomelli, et al data
Evidence of DNE & LOF in Giacomelli, et al data PubMed:30224644
Showed essentially no apoptosis activity in mutant cells PubMed:15037740
Non-functional allele according to T-A assays PubMed:12826609
PP3
BayesDel and AGVGD are concordant
PM1
Variant was observed 27 times in cancerhotspots.org
PS4_Supporting
1 proband meeting LFS classic criteria according to authors = 1 pt
Variant identified in LFS family where the proband was diagnosed with a soft tissue sarcoma at age 23 and breast cancer at age 43; family history of brain and ACC PubMed:16494995
PM2_Supporting
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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