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_000546.5(TP53):c.556G>A (p.Asp186Asn)

CA16615707

406601 (ClinVar)

Gene: TP53
Condition: Li-Fraumeni syndrome 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 8e43f0c3-2b97-4bca-97a7-e3afcfa1cd50

HGVS expressions

NM_000546.5:c.556G>A
NM_000546.5(TP53):c.556G>A (p.Asp186Asn)
NC_000017.11:g.7675056C>T
CM000679.2:g.7675056C>T
NC_000017.10:g.7578374C>T
CM000679.1:g.7578374C>T
NC_000017.9:g.7519099C>T
NG_017013.2:g.17495G>A
ENST00000269305.9:c.556G>A
ENST00000269305.8:c.556G>A
ENST00000359597.8:n.556G>A
ENST00000413465.6:n.556G>A
ENST00000420246.6:c.556G>A
ENST00000445888.6:c.556G>A
ENST00000455263.6:c.556G>A
ENST00000504290.5:c.160G>A
ENST00000504937.5:c.160G>A
ENST00000505014.5:n.812G>A
ENST00000509690.5:c.160G>A
ENST00000510385.5:c.160G>A
ENST00000514944.5:c.277G>A
ENST00000574684.1:n.64G>A
ENST00000610292.4:c.439G>A
ENST00000610538.4:c.439G>A
ENST00000610623.4:c.79G>A
ENST00000615910.4:n.523G>A
ENST00000617185.4:c.556G>A
ENST00000618944.4:c.79G>A
ENST00000619186.4:c.79G>A
ENST00000619485.4:c.439G>A
ENST00000620739.4:c.439G>A
ENST00000622645.4:c.439G>A
ENST00000635293.1:c.439G>A
NM_001126112.2:c.556G>A
NM_001126113.2:c.556G>A
NM_001126114.2:c.556G>A
NM_001126115.1:c.160G>A
NM_001126116.1:c.160G>A
NM_001126117.1:c.160G>A
NM_001126118.1:c.439G>A
NM_001276695.1:c.439G>A
NM_001276696.1:c.439G>A
NM_001276697.1:c.79G>A
NM_001276698.1:c.79G>A
NM_001276699.1:c.79G>A
NM_001276760.1:c.439G>A
NM_001276761.1:c.439G>A
NM_001276695.2:c.439G>A
NM_001276696.2:c.439G>A
NM_001276697.2:c.79G>A
NM_001276698.2:c.79G>A
NM_001276699.2:c.79G>A
NM_001276760.2:c.439G>A
NM_001276761.2:c.439G>A
NM_000546.6:c.556G>A
NM_001126112.3:c.556G>A
NM_001126113.3:c.556G>A
NM_001126114.3:c.556G>A
NM_001126115.2:c.160G>A
NM_001126116.2:c.160G>A
NM_001126117.2:c.160G>A
NM_001126118.2:c.439G>A
NM_001276695.3:c.439G>A
NM_001276696.3:c.439G>A
NM_001276697.3:c.79G>A
NM_001276698.3:c.79G>A
NM_001276699.3:c.79G>A
NM_001276760.3:c.439G>A
NM_001276761.3:c.439G>A

Likely Benign

Met criteria codes 2
BS3 BP4
Not Met criteria codes 22
PM3 PM1 PM4 PM5 PVS1 PM6 PM2 BA1 BS2 BS4 BS1 BP2 BP3 BP5 BP7 PS2 PS4 PS3 PS1 PP4 PP1 PP3

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
TP53 VCEP
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). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 (BP4). In summary, TP53 c.556G>A (p.Asp186Asn) 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.
Met criteria codes
BS3
Kato/Kotler transactivation class = functional; Giacomelli = notDNE_notLOF
Kato transactivation = 92.15 PubMed:12826609
A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = 0.095621624; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.307883038 PubMed:30224644
Kotler = -1.736005696 PubMed:29979965
BP4
aGVGD (zebrafish; Class C0) and BayesDel < 0.16 (BayesDel = -0.0517)
Not Met criteria codes
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
PM4
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
PVS1
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 of 251,328 alleles (0.00001) in gnomAD v2.1.1. Maximal subpopulation frequency of 2 of 34,586 (0.00006) in Latino subpopulation
BA1
Present in 2 of 251,328 alleles (0.00001) in gnomAD v2.1.1. Maximal subpopulation frequency of 2 of 34,586 (0.00006) in Latino subpopulation
BS2
Variant not present in FLOSSIES; no relevant cases in internal laboratory data
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Present in 2 of 251,328 alleles (0.00001) in gnomAD v2.1.1. Maximal subpopulation frequency of 2 of 34,586 (0.00006) in Latino subpopulation
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
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
BP7
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
Variant in one Hispanic F with breast dx 20s, no fam hx cancer, no HER2 info (Meet Chompret = 0.5 points) from internal lab data
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
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
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-03-25
Published on: 2021-09-24
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