rs758194998

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The ENST00000455263.6(TP53):c.1034C>T(p.Ser345Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,204,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S345S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

TP53
ENST00000455263.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.882

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 500 pathogenic changes around while only 113 benign (82%) in ENST00000455263.6

BP4

Computational evidence support a benign effect (MetaRNN=0.12897661).

BP6

Variant 17-7673226-G-A is Benign according to our data. Variant chr17-7673226-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 492648.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.993+309C>T		intron_variant		ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.993+309C>T		intron_variant		1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151436

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000183

AC:

AN:

163558

Hom.:

AF XY:

0.0000346

AC XY:

AN XY:

86648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000399

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000432

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000157

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1052776

Hom.:

Cov.:

AF XY:

0.0000187

AC XY:

AN XY:

534610

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000282

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000276

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000197

Gnomad4 OTH exome

AF:

0.0000644

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73898

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000863

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 06, 2017

The p.Ser345Leu variant in TP53 has not been previously reported as a germline v ariant in individuals with Li-Fraumeni syndrome. Data from large population stud ies is insufficient to assess the frequency of this variant. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. Of note, this variant is in the coding region of tr anscript NM_001126113.2, but not in other TP53 transcripts. In summary, the clin ical significance of the p.Ser345Leu variant is uncertain. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0030

BayesDel_noAF

Benign

-0.12

CADD

Benign

9.2

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0068

.;T;.;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.57

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Pathogenic

0.86

MutationTaster

Benign

1.0

N;N;N;N;N;N

PROVEAN

Benign

-0.010

.;.;N;.

REVEL

Benign

0.26

Sift

Pathogenic

0.0

.;.;D;.

Polyphen

0.99

.;.;D;.

Vest4

0.26

MutPred

0.29

.;.;Loss of disorder (P = 0.0033);.;

MVP

0.81

ClinPred

0.094

GERP RS

0.89

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