chr17-7673823-C-T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.797G>A(p.Gly266Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G266V) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
16
2
Clinical Significance
Conservation
PhyloP100: 7.91
Publications
289 publications found
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]
TP53 Gene-Disease associations (from GenCC):
- breast cancerInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- Li-Fraumeni syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
- Li-Fraumeni syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- adrenocortical carcinoma, hereditaryInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- bone marrow failure syndrome 5Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- colorectal cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- choroid plexus carcinomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PM1
In a hotspot region, there are 37 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 34 uncertain in NM_000546.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7673823-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 233303.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 17-7673823-C-T is Pathogenic according to our data. Variant chr17-7673823-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 161516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | MANE Select | c.797G>A | p.Gly266Glu | missense | Exon 8 of 11 | NP_000537.3 | ||
| TP53 | NM_001126112.3 | c.797G>A | p.Gly266Glu | missense | Exon 8 of 11 | NP_001119584.1 | |||
| TP53 | NM_001407262.1 | c.797G>A | p.Gly266Glu | missense | Exon 9 of 12 | NP_001394191.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | TSL:1 MANE Select | c.797G>A | p.Gly266Glu | missense | Exon 8 of 11 | ENSP00000269305.4 | ||
| TP53 | ENST00000445888.6 | TSL:1 | c.797G>A | p.Gly266Glu | missense | Exon 8 of 11 | ENSP00000391478.2 | ||
| TP53 | ENST00000610292.4 | TSL:1 | c.680G>A | p.Gly227Glu | missense | Exon 7 of 10 | ENSP00000478219.1 |
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 152024Hom.: 0 Cov.: 31
GnomAD3 genomes
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152024
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31
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461062Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726788
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
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1461062
Hom.:
Cov.:
33
AF XY:
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0
AN XY:
726788
African (AFR)
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0
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33462
American (AMR)
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0
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44536
Ashkenazi Jewish (ASJ)
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0
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26116
East Asian (EAS)
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0
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39676
South Asian (SAS)
AF:
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0
AN:
86130
European-Finnish (FIN)
AF:
AC:
0
AN:
53386
Middle Eastern (MID)
AF:
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0
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5768
European-Non Finnish (NFE)
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0
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1111618
Other (OTH)
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0
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60370
GnomAD4 genome 0.00 AC: 0AN: 152024Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74262
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
152024
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74262
African (AFR)
AF:
AC:
0
AN:
41392
American (AMR)
AF:
AC:
0
AN:
15236
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5174
South Asian (SAS)
AF:
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0
AN:
4828
European-Finnish (FIN)
AF:
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68008
Other (OTH)
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AC:
0
AN:
2084
Alfa
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ClinVar
ClinVar submissions as Germline
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts