NM_000546.6:c.701A>G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.701A>G(p.Tyr234Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Y234S) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
11
7
Clinical Significance
Conservation
PhyloP100: 1.63
Publications
261 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
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PM1
In a hotspot region, there are 44 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 29 uncertain in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7674262-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376690.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 17-7674262-T-C is Pathogenic according to our data. Variant chr17-7674262-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127820.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.701A>G | p.Tyr234Cys | missense | Exon 7 of 11 | NP_000537.3 | ||
| TP53 | NM_001126112.3 | c.701A>G | p.Tyr234Cys | missense | Exon 7 of 11 | NP_001119584.1 | |||
| TP53 | NM_001407262.1 | c.701A>G | p.Tyr234Cys | missense | Exon 8 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.701A>G | p.Tyr234Cys | missense | Exon 7 of 11 | ENSP00000269305.4 | ||
| TP53 | ENST00000445888.6 | TSL:1 | c.701A>G | p.Tyr234Cys | missense | Exon 7 of 11 | ENSP00000391478.2 | ||
| TP53 | ENST00000610292.4 | TSL:1 | c.584A>G | p.Tyr195Cys | missense | Exon 6 of 10 | ENSP00000478219.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
30
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251480 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
251480
AF XY:
Gnomad AFR exome
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Gnomad OTH exome
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461586Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727126
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1461586
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727126
African (AFR)
AF:
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0
AN:
33470
American (AMR)
AF:
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0
AN:
44722
Ashkenazi Jewish (ASJ)
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0
AN:
26134
East Asian (EAS)
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0
AN:
39696
South Asian (SAS)
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0
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86254
European-Finnish (FIN)
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AC:
0
AN:
53412
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111752
Other (OTH)
AF:
AC:
0
AN:
60380
GnomAD4 genome
GnomAD4 genome
Cov.:
30
Alfa
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ExAC
AF:
AC:
1
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic/Likely pathogenic
Revision:criteria provided, multiple submitters, no conflicts