rs1057520007

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000546.6(TP53):c.614A>T(p.Tyr205Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y205N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:16

Conservation

PhyloP100: 8.02

Publications

237 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 10 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 37 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 chr17-7674918-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 376686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.614A>T	p.Tyr205Phe	missense_variant	Exon 6 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.614A>T	p.Tyr205Phe	missense_variant	Exon 6 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:16

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Glioblastoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Carcinoma of esophagus

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Breast neoplasm

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Squamous cell lung carcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Papillary renal cell carcinoma type 1

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Uterine carcinosarcoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Multiple myeloma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Malignant neoplasm of body of uterus

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pancreatic adenocarcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lung adenocarcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neoplasm of brain

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Non-Hodgkin lymphoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neoplasm of the large intestine

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hepatocellular carcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.85

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

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.98

D;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

Pathogenic

3.0

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

PhyloP100

8.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.69

MutPred

0.85

Loss of phosphorylation at Y205 (P = 0.1118);Loss of phosphorylation at Y205 (P = 0.1118);.;.;.;.;.;.;.;Loss of phosphorylation at Y205 (P = 0.1118);.;Loss of phosphorylation at Y205 (P = 0.1118);Loss of phosphorylation at Y205 (P = 0.1118);Loss of phosphorylation at Y205 (P = 0.1118);.;.;Loss of phosphorylation at Y205 (P = 0.1118);.;.;.;.;

MVP

0.96

MPC

1.5

ClinPred

1.0

GERP RS

4.3

Varity_R

0.83

gMVP

0.56

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