17-7675208-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate

The NM_000546.6(TP53):c.404G>C(p.Cys135Ser) variant causes a missense change involving the alteration of a 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C135W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.90

Publications

0 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

TP53 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PS1

Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 37 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 41 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 chr17-7675208-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141762.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 17-7675208-C-G is Pathogenic according to our data. Variant chr17-7675208-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3893309.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.404G>C	p.Cys135Ser	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.404G>C	p.Cys135Ser	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 23, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: loss of growth suppression and non-functional transcriptional activation activity (PMID: 30224644, 29979965); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30224644, 29979965, 30661751, 15510160) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-9.2

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.

Sift4G

Pathogenic

0.0

D;T;D;D;D;T;D;T;T;T;T;T;T;D;T;D;D;.;.;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.;D;.;.

Vest4

0.83

MutPred

0.84

Gain of catalytic residue at C135 (P = 0.0613);Gain of catalytic residue at C135 (P = 0.0613);.;.;.;.;Gain of catalytic residue at C135 (P = 0.0613);.;Gain of catalytic residue at C135 (P = 0.0613);Gain of catalytic residue at C135 (P = 0.0613);Gain of catalytic residue at C135 (P = 0.0613);.;.;Gain of catalytic residue at C135 (P = 0.0613);.;.;.;.;Gain of catalytic residue at C135 (P = 0.0613);.;

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

5.5

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over