dbSNP rs1057519978: TP53:p.Cys141Gly (chr17-7675191-A-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000546.6(TP53):c.421T>G(p.Cys141Gly) variant causes a missense change. 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.

Frequency

Genomes: not found (cov: 33)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:12

Conservation

PhyloP100: 5.18

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.421T>G	p.Cys141Gly	missense_variant	Exon 5 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.421T>G	p.Cys141Gly	missense_variant	Exon 5 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:12

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Prostate adenocarcinoma

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

- -

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

- -

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

- -

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

- -

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

- -

Acute myeloid leukemia

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

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.87

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

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

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

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

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

3.2

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

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.6

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

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0040

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

0.93

MutPred

0.90

Loss of stability (P = 0.0368);Loss of stability (P = 0.0368);.;.;.;.;Loss of stability (P = 0.0368);.;Loss of stability (P = 0.0368);Loss of stability (P = 0.0368);Loss of stability (P = 0.0368);.;.;Loss of stability (P = 0.0368);.;.;.;.;Loss of stability (P = 0.0368);.;

MVP

0.99

MPC

1.8

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over