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]
Link to SEPIO compliant JSON-LD document
  • See Evidence submitted by expert panel for details.

Variant: NM_001126112.2(TP53):c.998G>A (p.Arg333His)

CA000533

142273 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: d8de06fc-22f0-4978-9c21-a8d7b365d2c9
Approved on: 2021-05-06
Published on: 2021-06-16

HGVS expressions

NM_001126112.2:c.998G>A
NM_001126112.2(TP53):c.998G>A (p.Arg333His)
ENST00000269305.9:c.998G>A
ENST00000269305.8:c.998G>A
ENST00000359597.8:n.993+2824G>A
ENST00000413465.6:n.782+3470G>A
ENST00000420246.6:c.*105G>A
ENST00000445888.6:c.998G>A
ENST00000455263.6:c.*17G>A
ENST00000504290.5:c.*17G>A
ENST00000504937.5:c.602G>A
ENST00000510385.5:c.*105G>A
ENST00000576024.1:n.54-1021G>A
ENST00000610292.4:c.881G>A
ENST00000610538.4:c.*17G>A
ENST00000610623.4:c.*17G>A
ENST00000615910.4:n.965G>A
ENST00000617185.4:c.*105G>A
ENST00000618944.4:c.*105G>A
ENST00000619186.4:c.521G>A
ENST00000619485.4:c.881G>A
ENST00000620739.4:c.881G>A
ENST00000622645.4:c.*105G>A
ENST00000635293.1:c.881G>A
NM_000546.5:c.998G>A
NM_001126113.2:c.*17G>A
NM_001126114.2:c.*105G>A
NM_001126115.1:c.602G>A
NM_001126116.1:c.*105G>A
NM_001126117.1:c.*17G>A
NM_001126118.1:c.881G>A
NM_001276695.1:c.*17G>A
NM_001276696.1:c.*105G>A
NM_001276697.1:c.521G>A
NM_001276698.1:c.*105G>A
NM_001276699.1:c.*17G>A
NM_001276760.1:c.881G>A
NM_001276761.1:c.881G>A
NM_001276695.2:c.*17G>A
NM_001276696.2:c.*105G>A
NM_001276697.2:c.521G>A
NM_001276698.2:c.*105G>A
NM_001276699.2:c.*17G>A
NM_001276760.2:c.881G>A
NM_001276761.2:c.881G>A
NM_000546.6:c.998G>A
NM_001126112.3:c.998G>A
NM_001126113.3:c.*17G>A
NM_001126114.3:c.*105G>A
NM_001126115.2:c.602G>A
NM_001126116.2:c.*105G>A
NM_001126117.2:c.*17G>A
NM_001126118.2:c.881G>A
NM_001276695.3:c.*17G>A
NM_001276696.3:c.*105G>A
NM_001276697.3:c.521G>A
NM_001276698.3:c.*105G>A
NM_001276699.3:c.*17G>A
NM_001276760.3:c.881G>A
NM_001276761.3:c.881G>A
NC_000017.11:g.7670711C>T
CM000679.2:g.7670711C>T
NC_000017.10:g.7574029C>T
CM000679.1:g.7574029C>T
NC_000017.9:g.7514754C>T
NG_017013.2:g.21840G>A

Likely Benign

Met criteria codes 3
BP4 BS2_Supporting BS3
Not Met criteria codes 9
BA1 PS4 PS3 PS1 PP3 PM1 PM5 PM2 BS1

Evidence Links 5

Expert Panel

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 C0 or Class C15 (BP4). Transactivation assays show functional transactivation according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. and normal tetramer formation according to Kawaguchi, et al. (BS3; PMID: 12826609, 30224644,16007150). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Invitae). In summary, TP53 c.998G>A (p.Arg333His) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting.
Met criteria codes
BP4
aGVGD C0; BayesDel = -0.0924
BS2_Supporting
Not in FLOSSIES. 6 unaffected 60+ females from Invitae data. Also 1 60+ from Color and 1 60+ from Ambry.
BS3
Kato functional; no evidence of DNE or LOF by Giacomelli; Kotler N/A; Kawaguchi shows normal tetramer formation.
Demonstrates normal tetramer formation. PubMed:16007150
Functional activity in yeast transactivation assay PubMed:12826609
No evidence of DNE or LOF PubMed:30224644
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Germline cases not found in literature. One case of Chompret from Invitae = 0.5 pts.
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Not in cancerhotspots.com
Observed in KIT mutant GIST tumor tissue at an AF of 34% PubMed:28028119
Basis of cancerhotspots.com PubMed:26619011
PM5
R333C (ID: 184745, VUSx6)
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
12/267594 (0.0045%) across gnomAD (non-cancer), including 6/117748 (0.005%) in European (non-Finnish)
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