17-7674237-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000546.6(TP53):​c.726C>A​(p.Cys242*) variant causes a stop gained 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C242C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

TP53
NM_000546.6 stop_gained

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.22

Publications

3 publications found
Variant links:
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 cancer
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • Li-Fraumeni syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
  • Li-Fraumeni syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
  • adrenocortical carcinoma, hereditary
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
  • sarcoma
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • bone marrow failure syndrome 5
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • colorectal cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • choroid plexus carcinoma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-7674237-G-T is Pathogenic according to our data. Variant chr17-7674237-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1460346.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.726C>A p.Cys242* stop_gained Exon 7 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.726C>A p.Cys242* stop_gained Exon 7 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:1
Jun 11, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 20127978). This sequence change creates a premature translational stop signal (p.Cys242*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
37
DANN
Uncertain
0.99
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.97
D
PhyloP100
2.2
Vest4
0.94
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Mutation Taster
=0/200
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs375874539; hg19: chr17-7577555; COSMIC: COSV53034631; COSMIC: COSV53034631; API