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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000546.5(TP53):c.461G>A (p.Gly154Asp)

CA002547

237950 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8aa4ca01-1c6e-4192-b46b-2f5debbca3dc
Approved on: 2021-08-26
Published on: 2021-09-24

HGVS expressions

NM_000546.5:c.461G>A
NM_000546.5(TP53):c.461G>A (p.Gly154Asp)
ENST00000269305.9:c.461G>A
ENST00000269305.8:c.461G>A
ENST00000359597.8:n.461G>A
ENST00000413465.6:n.461G>A
ENST00000420246.6:c.461G>A
ENST00000445888.6:c.461G>A
ENST00000455263.6:c.461G>A
ENST00000504290.5:c.65G>A
ENST00000504937.5:c.65G>A
ENST00000505014.5:n.717G>A
ENST00000508793.5:c.461G>A
ENST00000509690.5:c.65G>A
ENST00000510385.5:c.65G>A
ENST00000514944.5:c.182G>A
ENST00000610292.4:c.344G>A
ENST00000610538.4:c.344G>A
ENST00000610623.4:c.-17G>A
ENST00000615910.4:n.428G>A
ENST00000617185.4:c.461G>A
ENST00000618944.4:c.-17G>A
ENST00000619186.4:c.-17G>A
ENST00000619485.4:c.344G>A
ENST00000620739.4:c.344G>A
ENST00000622645.4:c.344G>A
ENST00000635293.1:c.344G>A
NM_001126112.2:c.461G>A
NM_001126113.2:c.461G>A
NM_001126114.2:c.461G>A
NM_001126115.1:c.65G>A
NM_001126116.1:c.65G>A
NM_001126117.1:c.65G>A
NM_001126118.1:c.344G>A
NM_001276695.1:c.344G>A
NM_001276696.1:c.344G>A
NM_001276697.1:c.-17G>A
NM_001276698.1:c.-17G>A
NM_001276699.1:c.-17G>A
NM_001276760.1:c.344G>A
NM_001276761.1:c.344G>A
NM_001276695.2:c.344G>A
NM_001276696.2:c.344G>A
NM_001276697.2:c.-17G>A
NM_001276698.2:c.-17G>A
NM_001276699.2:c.-17G>A
NM_001276760.2:c.344G>A
NM_001276761.2:c.344G>A
NM_000546.6:c.461G>A
NM_001126112.3:c.461G>A
NM_001126113.3:c.461G>A
NM_001126114.3:c.461G>A
NM_001126115.2:c.65G>A
NM_001126116.2:c.65G>A
NM_001126117.2:c.65G>A
NM_001126118.2:c.344G>A
NM_001276695.3:c.344G>A
NM_001276696.3:c.344G>A
NM_001276697.3:c.-17G>A
NM_001276698.3:c.-17G>A
NM_001276699.3:c.-17G>A
NM_001276760.3:c.344G>A
NM_001276761.3:c.344G>A
NC_000017.11:g.7675151C>T
CM000679.2:g.7675151C>T
NC_000017.10:g.7578469C>T
CM000679.1:g.7578469C>T
NC_000017.9:g.7519194C>T
NG_017013.2:g.17400G>A

Uncertain Significance

Met criteria codes 3
BS2_Supporting BS3_Supporting PP3_Moderate
Not Met criteria codes 19
PP4 PP1 PP2 BS4 BS1 BP5 BP2 BP4 BP1 PS2 PS4 PS3 PS1 BA1 PM6 PM2 PM3 PM1 PM5

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 15 or higher (PP3_Moderate). However, transactivation assays show partially functional variant 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_Supporting; PMID: 12826609, 30224644). This variant has been observed in 2 60+ year old females without a cancer diagnosis (BS2_Supporting; PMID: internal expert panel member contributor). In summary, the clinical significance of TP53 c.461G>A; p.Gly154Asp is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS2_supporting, BS3_Supporting, PP3_Moderate.
Met criteria codes
BS2_Supporting
Not identified in FLOSSIES, identified in 2 (heterozygous) women 60+ no cancer from 1 laboratory (submitted internal lab data)
BS3_Supporting
Retained partial function by Kato (66.5%), notDNE_notLOF by Giacomelli, and not_LOF by Kotler.
PP3_Moderate
Align-GVGD (Class C65) and BayesDel (0.2733)
Not Met criteria codes
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
Present in 2/251272 (0.0008%) total alleles gnomAD.
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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