rs758194998

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_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. 14/18 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

Publications

17 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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 VariationId is 492648.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.993+309C>T		intron_variant	Intron 9 of 10	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.993+309C>T		intron_variant	Intron 9 of 10	1	NM_000546.6	ENSP00000269305.4

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

GnomAD2 exomes

AF:

0.0000183

AC:

AN:

163558

AF XY:

0.0000346

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 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

African (AFR)

AF:

0.00

AC:

AN:

24854

American (AMR)

AF:

0.0000282

AC:

AN:

35462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22998

East Asian (EAS)

AF:

0.00

AC:

AN:

35032

South Asian (SAS)

AF:

0.0000276

AC:

AN:

72506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5036

European-Non Finnish (NFE)

AF:

0.0000197

AC:

AN:

760514

Other (OTH)

AF:

0.0000644

AC:

AN:

46610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73898

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41174

American (AMR)

AF:

0.00

AC:

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000226

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

Feb 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Mar 03, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.0030

BayesDel_noAF

Benign

-0.12

CADD

Benign

9.2

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;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

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

0.88

PROVEAN

Benign

0.0

.;.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Pathogenic

0.0

.;.;.;.

Vest4

0.26

ClinPred

0.094

GERP RS

0.89

PromoterAI

-0.011

Neutral

(source)

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over