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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.847C>T (p.Arg283Cys)

CA000457

127824 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 0b9a7a17-b7b8-4223-bd64-69617a2d691d
Approved on: 2022-03-18
Published on: 2022-03-18

HGVS expressions

NM_000546.5:c.847C>T
NM_000546.5(TP53):c.847C>T (p.Arg283Cys)
NC_000017.11:g.7673773G>A
CM000679.2:g.7673773G>A
NC_000017.10:g.7577091G>A
CM000679.1:g.7577091G>A
NC_000017.9:g.7517816G>A
NG_017013.2:g.18778C>T
ENST00000503591.2:c.847C>T
ENST00000508793.6:c.847C>T
ENST00000509690.6:c.451C>T
ENST00000514944.6:c.568C>T
ENST00000604348.6:c.826C>T
ENST00000269305.9:c.847C>T
ENST00000269305.8:c.847C>T
ENST00000359597.8:c.847C>T
ENST00000413465.6:c.782+408C>T
ENST00000420246.6:c.847C>T
ENST00000445888.6:c.847C>T
ENST00000455263.6:c.847C>T
ENST00000504290.5:c.451C>T
ENST00000504937.5:c.451C>T
ENST00000509690.5:c.451C>T
ENST00000510385.5:c.451C>T
ENST00000610292.4:c.730C>T
ENST00000610538.4:c.730C>T
ENST00000610623.4:c.370C>T
ENST00000615910.4:c.814C>T
ENST00000617185.4:c.847C>T
ENST00000618944.4:c.370C>T
ENST00000619186.4:c.370C>T
ENST00000619485.4:c.730C>T
ENST00000620739.4:c.730C>T
ENST00000622645.4:c.730C>T
ENST00000635293.1:c.730C>T
NM_001126112.2:c.847C>T
NM_001126113.2:c.847C>T
NM_001126114.2:c.847C>T
NM_001126115.1:c.451C>T
NM_001126116.1:c.451C>T
NM_001126117.1:c.451C>T
NM_001126118.1:c.730C>T
NM_001276695.1:c.730C>T
NM_001276696.1:c.730C>T
NM_001276697.1:c.370C>T
NM_001276698.1:c.370C>T
NM_001276699.1:c.370C>T
NM_001276760.1:c.730C>T
NM_001276761.1:c.730C>T
NM_001276695.2:c.730C>T
NM_001276696.2:c.730C>T
NM_001276697.2:c.370C>T
NM_001276698.2:c.370C>T
NM_001276699.2:c.370C>T
NM_001276760.2:c.730C>T
NM_001276761.2:c.730C>T
NM_000546.6:c.847C>T
NM_001126112.3:c.847C>T
NM_001126113.3:c.847C>T
NM_001126114.3:c.847C>T
NM_001126115.2:c.451C>T
NM_001126116.2:c.451C>T
NM_001126117.2:c.451C>T
NM_001126118.2:c.730C>T
NM_001276695.3:c.730C>T
NM_001276696.3:c.730C>T
NM_001276697.3:c.370C>T
NM_001276698.3:c.370C>T
NM_001276699.3:c.370C>T
NM_001276760.3:c.730C>T
NM_001276761.3:c.730C>T
More

Likely Benign

Met criteria codes 4
PP3 BS3 BS2 PS4_Supporting
Not Met criteria codes 5
PM2 BA1 PM1 BS1 BP5

Evidence Links 0

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 25 or higher (PP3). This variant has been reported in 3 probands meeting Chompret criteria (PS4_Supporting; internal laboratory contributor (SCV000183772.7). However, this variant has been observed in greater than 8 60+ year old females without a cancer diagnosis (BS2; internal laboratory contributors: SCV000183772.7, SCV000254640.10) and has been seen many times by VCEP lab contributors in individuals not meeting LFS criteria. Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). The TP53 VCEP reviewed the conflicting evidence (PP3 and PS4_Supporting) and felt it did not override the Likely Benign classification in this case. In summary, the TP53 VCEP classified this variant as likely benign. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PP3, BS3, BS2.
Met criteria codes
PP3
BayesDel suggests pathogenic & AGVGD = Class C55
BS3
Transactivation assay shows retained function and there is no dominant negative effects or evidence of LOF in Giacomelli data
BS2
Ambry labs has seen internally 145 times with no cases meeting Classical criteria and 3 cases meeting Chompret. They have seen in enough cancer free females by age 60 to apply BS2 at full weight. Invitae has seen this variant in over 200 internal cases with no cases meeting Classical criteria.
PS4_Supporting
Megan 2/2022: Ambry reports 3 cases meeting Chompret = 1.5 points
Not Met criteria codes
PM2
Present in gnomAD
BA1
Present in gnomAD
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Present in gnomAD
BP5
This variant was found in one woman with breast cancer at 29 and ovarian cancer at 56 who also had a pathogenic variant in BRCA2, but this does not rule out the pathogencity of this variant.
Curation History
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